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1. Differential intracellular trafficking of extracellular vesicles in microglia and astrocytes

Author: Pantazopoulou, Marina, Lamprokostopoulou, Agaristi, Karampela, Dimitra Sotiria, Alexaki, Anastasia, Delis, Anastasios, Coens, Audrey, Samiotaki, Martina, Kriebardis, Anastasios, Melki, Ronald, Pagakis, Stamatis, Stefanis, Leonidas, Vekrellis, Kostas, Biomedical Research Foundation of the Academy of Athens (BRFAA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), and University of West Attica [Athens] (UNIWA)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; Extracellular vesicles (EVs) have emerged as key players in cell-to-cell communication in both physiological and pathological processes in the Central Nervous System. Thus far, the intracellular pathways involved in uptake and trafficking of EVs within different cell types of the brain are poorly understood. In our study, the endocytic processes and subcellular sorting of EVs were investigated in primary glial cells, particularly linked with the EV-associated α-synuclein (α-syn) transmission. Mouse microglia and astrocytic primary cultures were incubated with DiI-stained mouse brain-derived EVs. The internalization and trafficking pathways were analyzed in cells treated with pharmacological reagents that block the major endocytic pathways. Brain-derived EVs were internalized by both glial cell types; however, uptake was more efficient in microglia than in astrocytes. Colocalization of EVs with early and late endocytic markers (Rab5, Lamp1) indicated that EVs are sorted to endo-lysosomes for subsequent processing. Blocking actin-dependent phagocytosis and/or macropinocytosis with Cytochalasin D or EIPA inhibited EV entry into glial cells, whereas treatment with inhibitors that strip cholesterol off the plasma membrane, induced uptake, however differentially altered endosomal sorting. EV-associated fibrillar α-Syn was efficiently internalized and detected in Rab5- and Lamp1-positive compartments within microglia. Our study strongly suggests that EVs enter glial cells through phagocytosis and/or macropinocytosis and are sorted to endo-lysosomes for subsequent processing. Further, brain-derived EVs serve as scavengers and mediate cell-to-glia transfer of pathological α-Syn which is also targeted to the endolysosomal pathway, suggesting a beneficial role in microglia-mediated clearance of toxic protein aggregates, present in numerous neurodegenerative diseases.
Published: 2023

2. Assessing potential correlation between T 2 relaxation and diffusion of lactate in the mouse brain

Author: Eloïse Mougel, Sophie Malaquin, Julien Valette, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: intracellular/extracellular, lactate, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, apparent diffusivity, compartmentation, T2 relaxation, Radiology, Nuclear Medicine and imaging, apparent kurtosis, DW-MRS, frequency-selective sequence
Abstract: International audience; While diffusion and T 2 relaxation are intertwined, little or no correlation exists between diffusion and T 2 relaxation of intracellular metabolites in the rodent brain, as measured by diffusion-weighted MRS at different TEs. However, situation might be different for lactate, since it is present in both extracellular and intracellular spaces, which exhibit different diffusion properties and may also exhibit different T 2. Such a TE dependence would be crucial to account for when interpreting or modeling lactate diffusion. Here we propose to take advantage of a new diffusion sequence, where J-modulation of lactate is canceled even at long TE, thus retaining excellent signal, to assess potential T 2 dependence on diffusion of lactate in the mouse brain. Methods: Using a frequency-selective diffusion-weighted spin-echo sequence that removes J-modulation at 1.3 ppm, thus preserving lactate signal even at long TE, we investigate the effect of TE between 50.9 and 110.9 ms (while keeping diffusion time constant) on apparent diffusivity and kurtosis in the mouse brain. Results: Regardless of the metabolites, no difference appears for the diffusion-weighted signal attenuation with increasing TE. For lactate, apparent diffusivity and kurtosis remain unchanged as TE increases. Conclusion: No significant TE dependence of diffusivity and kurtosis is measured for lactate in the 50-110 ms TE range, confirming that potential T 2 effects can be ignored when interpreting or modeling lactate diffusion.
Published: 2022

3. Upregulation of astroglial connexin 30 impairs hippocampal synaptic activity and recognition memory

Author: Eléonore Hardy, Julien Moulard, Augustin Walter, Pascal Ezan, Alexis-Pierre Bemelmans, Franck Mouthon, Mathieu Charvériat, Nathalie Rouach, Armelle Rancillac, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Ecole doctorale Cerveau Cognition et Comportement [Paris] (ED 158 - 3C), Sorbonne Université (SU), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Theranexus [Lyon], and Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris)
Subjects: General Immunology and Microbiology, General Neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology
Abstract: International audience; Astrocytes crucially contribute to synaptic physiology and information processing. One of their key characteristics is to express high levels of connexins (Cxs), the gap junction–forming protein. Among them, Cx30 displays specific properties since it is postnatally expressed and dynamically upregulated by neuronal activity and modulates cognitive processes by shaping synaptic and network activities, as recently shown in knockout mice. However, it remains unknown whether local and selective upregulation of Cx30 in postnatal astrocytes within a physiological range modulates neuronal activities in the hippocampus. We here show in mice that, whereas Cx30 upregulation increases the connectivity of astroglial networks, it decreases spontaneous and evoked synaptic transmission. This effect results from a reduced neuronal excitability and translates into an alteration in the induction of synaptic plasticity and an in vivo impairment in learning processes. Altogether, these results suggest that astroglial networks have a physiologically optimized size to appropriately regulate neuronal functions.
Published: 2023

4. Multi-site-specific isotopic labeling accelerates high-resolution structural investigations of pathogenic huntingtin exon-1

Author: Elena-Real, Carlos, Urbanek, Annika, Lund, Xamuel, Morató, Anna, Sagar, Amin, Fournet, Aurélie, Estaña, Alejandro, Bellande, Tracy, Allemand, Frédéric, Cortés, Juan, Sibille, Nathalie, Melki, Ronald, Bernadó, Pau, Centre de Biologie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut Laue-Langevin (ILL), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), ANR-17-JPCD-0002,TransPathND,Intraneuronal transport-related pathways across neurodegenerative diseases(2017), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0012,EpiGenMed,From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow(2010), and European Project: 648030,H2020,ERC-2014-CoG,chemREPEAT(2015)
Subjects: nuclear magnetic resonance, tRNA suppression, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Structural Biology, huntingtin, conformational ensemble, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, intrinsically disordered proteins, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], poly-Q, Molecular Biology, isotopic labeling, Huntington’s disease
Abstract: Huntington's disease neurodegeneration occurs when the number of consecutive glutamines in the huntingtin exon-1 (HTTExon1) exceeds a pathological threshold of 35. The sequence homogeneity of HTTExon1 reduces the signal dispersion in NMR spectra, hampering its structural characterization. By simultaneously introducing three isotopically labeled glutamines in a site-specific manner in multiple concatenated samples, 18 glutamines of a pathogenic HTTExon1 with 36 glutamines were unambiguously assigned. Chemical shift analyses indicate the α-helical persistence in the homorepeat and the absence of an emerging toxic conformation around the pathological threshold. Using the same type of samples, the recognition mechanism of Hsc70 molecular chaperone has been investigated, indicating that it binds to the N17 region of HTTExon1, inducing the partial unfolding of the poly-Q. The proposed strategy facilitates high-resolution structural and functional studies in low-complexity regions.
Published: 2023

5. Rééducation de la mémoire de travail après un traumatisme crânien : Etudes de cas cognitives et IRM (PLASTIM-MDTC)

Author: Mazo, Guillaume, Pantaléo, Stéphanie, Picq, Jean-Luc, Hertz-Pannier, Lucie, Brunet-Gouet, Eric, Barbot, Frederic, Azouvi, Philippe, Vallat-Azouvi, Claire, Université Paris 8 Vincennes-Saint-Denis - UFR de psychologie, Université Paris 8 Vincennes-Saint-Denis (UP8), Fonctionnement et Dysfonctionnement Cognitifs : Les âges de la vie (DysCo), Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN), Antenne UEROS-UGECAMIDF - Hôpital Raymond Poincarré [Garches], Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche en NeuroImagerie Applicative Clinique et Translationnelle (UNIACT), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CH Versailles] (CeRéMAIA - Hôpital André Mignot), Centre Hospitalier de Versailles André Mignot (CHV), Centre d’Investigation Clinique 1429 [Garches] (CIC 1429), Hôpital Raymond Poincaré [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Hôpital Raymond Poincaré [AP-HP], Recherche PLASTIM-MDTC financée par l'IRME (institut pour la recherche sur la moelle épinière et l'encéphale)Travail dans le cadre d'une thèse financée par contrat doctoral UPL (Université Paris Lumière), and International Brain Injury Association (IBIA)
Subjects: Traumatic Brain Injury TBI, [SCCO]Cognitive science, FMRI-functional magnetic resonance imaging, [SCCO.NEUR]Cognitive science/Neuroscience, Rehabilitation, [SCCO.PSYC]Cognitive science/Psychology, Working memory
Abstract: International audience; INTRODUCTION: Working memory (WM) disorders often persist long time after an acquired brain injury (ABI), and involve difficulties in daily life (Azouvi et al. 2017). For several decades, methods of cognitive rehabilitation and training in healthy subjects have been developed. But contrary to the literature on healthy subjects (Papa et al, 2020), to date there are still very few studies evaluating the cerebral correlates of rehabilitation in patients with ABI. The objective of this study is to study the effects of cognitive rehabilitation on brain plasticity. METHODS: PLASTIM-MDTC is a study with a repeated single case experimental design on individuals with moderate to severe TBI. After two baseline cognitive assessments, patients underwent WM rehabilitation during 3 months (3/week). The effectiveness of rehabilitation was evaluated post-rehabilitation and after 3 months. A multimodal MRI was performed before and after rehabilitation. PRELIMINARY RESULTS: We will present the results obtained for 3 patients. The results showed an effectiveness of rehabilitation on the behavioral level and an evolution of the functional activation profile on MRI during an n-back task. Primary outcome measures showed an average improvement in the Brown-Peterson task and a mean decrease in complaints in daily life related to WM. However, the evolution profile differed from one patient to another, with higher improvement in patients with more severe baseline impairments, variability between outcome measure in post and 3 months follow-up assessment, and different fMRI n-back evolution profile (decrease or increase). Interestingly, a far transfer in long-term memory appears in some patients, especially during the 3-months follow-up. DISCUSSION-CONCLUSION: The preliminary results of the PLASTIM study are in agreement with those observed in the repeated case studies of Hubacher et al (2015) on MS patients. The continuation of this research should make it possible to study the different evolution profiles and contribute to the search for early markers of the effectiveness of rehabilitation.
Published: 2023

6. Melanophages give rise to hyperreflective foci in AMD, a disease-progression marker

Author: Augustin, Sebastien, Lam, Marion, Lavalette, Sophie, Verschueren, Anna, Blond, Frédéric, Forster, Valérie, Przegralek, Lauriane, He, Zhiguo, Lewandowski, Daniel, Bemelmans, Alexis-Pierre, Picaud, Serge, Sahel, José-Alain, Mathis, Thibaud, Paques, Michel, Thuret, Gilles, Guillonneau, Xavier, Delarasse, Cécile, Sennlaub, Florian, Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Centre d'investigation clinique Quinze-Vingts [CHNO] (CIC1423 - CIC QUINZE-VINGTS), Institut Hospitalo-Universitaire FOReSIGHT (IHU FOReSIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-Sorbonne Université (SU), Biologie, Ingénierie et Imagerie pour l'Ophtalmologie (BIIO), Université Jean Monnet - Saint-Étienne (UJM), Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Matériaux, ingénierie et science [Villeurbanne] (MATEIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cellular and Molecular Neuroscience, Neuroinflammation, Neurology, Macrophage, Age-related macular degeneration, [SDV]Life Sciences [q-bio], General Neuroscience, Immunology, CD47
Abstract: Retinal melanosome/melanolipofuscin-containing cells (MCCs), clinically visible as hyperreflective foci (HRF) and a highly predictive imaging biomarker for the progression of age-related macular degeneration (AMD), are widely believed to be migrating retinal pigment epithelial (RPE) cells. Using human donor tissue, we identify the vast majority of MCCs as melanophages, melanosome/melanolipofuscin-laden mononuclear phagocytes (MPs). Using serial block-face scanning electron microscopy, RPE flatmounts, bone marrow transplantation and in vitro experiments, we show how retinal melanophages form by the transfer of melanosomes from the RPE to subretinal MPs when the “don’t eat me” signal CD47 is blocked. These melanophages give rise to hyperreflective foci in Cd47−/−-mice in vivo, and are associated with RPE dysmorphia similar to intermediate AMD. Finally, we show that Cd47 expression in human RPE declines with age and in AMD, which likely participates in melanophage formation and RPE decline. Boosting CD47 expression in AMD might protect RPE cells and delay AMD progression.
Published: 2023

7. Detection of antibodies against the huntingtin protein in human plasma

Author: Denis, Hélèna L., Alpaugh, Melanie, Alvarez, Claudia P., Fenyi, Alexis, Barker, Roger A., Chouinard, Sylvain, Arrowsmith, Cheryl H., Melki, Ronald, Labib, Richard, Harding, Rachel J., Cicchetti, Francesca, Cicchetti, Francesca [0000-0001-5490-1961], Apollo - University of Cambridge Repository, Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Structural Genomics Consortium, University of Toronto, Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), University of Cambridge [UK] (CAM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Princess Margaret Hospital, École Polytechnique de Montréal (EPM), Department of Pharmacology and Toxicology [Toronto], and ANR-17-JPCD-0002,TransPathND,Intraneuronal transport-related pathways across neurodegenerative diseases(2017)
Subjects: Pharmacology, Huntingtin Protein, [SDV]Life Sciences [q-bio], Neurodegenerative Diseases, Cell Biology, Antibodies, Plasma, Cellular and Molecular Neuroscience, Huntington Disease, Humans, Molecular Medicine, Original Article, Human samples, Molecular Biology, Huntington’s disease
Abstract: Funder: Huntington Society of Canada; doi: http://dx.doi.org/10.13039/100009836, Funder: NIHR BioResource; doi: http://dx.doi.org/10.13039/100017751, Funder: Huntington's Disease Society of America; doi: http://dx.doi.org/10.13039/100000887, Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder resulting from a CAG expansion in the huntingtin (HTT) gene, which leads to the production and accumulation of mutant huntingtin (mHTT). While primarily considered a disorder of the central nervous system, multiple changes have been described to occur throughout the body, including activation of the immune system. In other neurodegenerative disorders, activation of the immune system has been shown to include the production of antibodies against disease-associated pathological proteins. However, the existence of mHTT-targeted antibodies has never been reported. In this study, we assessed the presence and titer of antibodies recognizing HTT/mHTT in patients with HD (n = 66) and age- and gender-matched healthy controls (n = 66) using a combination of Western blotting and ELISA. Together, these analyses revealed that antibodies capable of recognizing HTT/mHTT were detectable in the plasma samples of all participants, including healthy controls. When antibody levels were monitored at different disease stages, it was observed that antibodies against full-length mHTT were highest in patients with severe disease while antibodies against HTTExon1 were elevated in patients with mild disease. Combined, these results suggest that antibodies detecting different forms of mHTT peak at different disease stages.
Published: 2023

8. AAV-mediated expression of a new conformational anti-aggregated α-synuclein antibody prolongs survival in a genetic model of α-synucleinopathies

Author: Düchs, Matthias, Blazevic, Dragica, Rechtsteiner, Philipp, Kenny, Cynthia, Lamla, Thorsten, Low, Sarah, Savistchenko, Jimmy, Neumann, Manuela, Melki, Ronald, Schönberger, Tanja, Stierstorfer, Birgit, Wyatt, David, Igney, Frederik, Ciossek, Thomas, Boehringer Ingelheim Pharma GmbH & Co. KG, Boehringer Ingelheim, Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Universitätsklinikum Tübingen - University Hospital of Tübingen, and Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
Subjects: [SDV]Life Sciences [q-bio], ddc:610
Abstract: International audience; Prion-like transmission of pathology in α-synucleinopathies like Parkinson’s disease or multiple system atrophy is increasingly recognized as one potential mechanism to address disease progression. Active and passive immunotherapies targeting insoluble, aggregated α-synuclein are already being actively explored in the clinic with mixed outcomes so far. Here, we report the identification of 306C7B3, a highly selective, aggregate-specific α-synuclein antibody with picomolar affinity devoid of binding to the monomeric, physiologic protein. 306C7B3 binding is Ser129-phosphorylation independent and shows high affinity to several different aggregated α-synuclein polymorphs, increasing the likelihood that it can also bind to the pathological seeds assumed to drive disease progression in patients. In support of this, highly selective binding to pathological aggregates in postmortem brains of MSA patients was demonstrated, with no staining in samples from other human neurodegenerative diseases. To achieve CNS exposure of 306C7B3, an adeno-associated virus (AAV) based approach driving expression of the secreted antibody within the brain of (Thy-1)-[A30P]-hα-synuclein mice was used. Widespread central transduction after intrastriatal inoculation was ensured by using the AAV2HBKO serotype, with transduction being spread to areas far away from the inoculation site. Treatment of (Thy-1)-[A30P]-hα-synuclein mice at the age of 12 months demonstrated significantly increased survival, with 306C7B3 concentration reaching 3.9 nM in the cerebrospinal fluid. These results suggest that AAV-mediated expression of 306C7B3, targeting extracellular, presumably disease-propagating aggregates of α-synuclein, has great potential as a disease-modifying therapy for α-synucleinopathies as it ensures CNS exposure of the antibody, thereby mitigating the selective permeability of the blood-brain barrier.
Published: 2023

9. Rééducation de la mémoire de travail après un traumatisme crânien : liens entre cognition et IRM

Author: Mazo, Guillaume, Pantaléo, Stéphanie, Picq, Jean-Luc, Hertz-Pannier, Lucie, Brunet-Gouet, Eric, Azouvi, Philippe, Vallat-Azouvi, Claire, Université Paris 8 Vincennes-Saint-Denis - UFR de psychologie, Université Paris 8 Vincennes-Saint-Denis (UP8), Fonctionnement et Dysfonctionnement Cognitifs : Les âges de la vie (DysCo), Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN), Antenne UEROS-UGECAMIDF - Hôpital Raymond Poincarré [Garches], Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche en NeuroImagerie Applicative Clinique et Translationnelle (UNIACT), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CH Versailles] (CeRéMAIA - Hôpital André Mignot), Centre Hospitalier de Versailles André Mignot (CHV), Hôpital Raymond Poincaré [AP-HP], Recherche PLASTIM-MDTC financée par l'IRME (institut pour la recherche sur la moelle épinière et l'encéphale)Travail dans le cadre d'une thèse financée par contrat doctoral UPL (Université Paris Lumière), and Ecole Doctorale n°224 Cognition, langage, interaction - Université Paris 8
Subjects: [SCCO]Cognitive science, Rééducation Cognitive, Traumatisme crânien TC, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.PSYC]Cognitive science/Psychology, Mémoire de travail, IRMf
Abstract: National audience; INTRODUCTION: Des troubles de la mémoire de travail (MDT) persistent souvent à long terme après une lésion cérébrale acquise, et engendrent des difficultés en vie quotidienne (Azouvi et al., 2017). Contrairement à la littérature sur le sujet sain (Papa et al., 2020), il n’existe encore à ce jour que très peu d’études évaluant les corrélats cérébraux de la rééducation chez le patient cérébrolésé. L’objectif de cette étude est donc d’étudier les effets de la rééducation cognitive sur la plasticité cérébrale.METHODE: L’étude PLASTIM-MDTC est une étude en cas unique répétés sur des patients TC modéré à sévères. Après deux évaluations cognitives en ligne de base, les patients ont bénéficié d’une rééducation de la MDT pendant 3 mois (3/sem). L’efficacité de la rééducation à été évalué en post rééducation et après 3 mois. Une IRM multimodale est effectuée avant et après rééducation.RESULTATS PRELIMINAIRES : Les résultats montrent une efficacité de la rééducation sur le plan comportemental et une évolution du profil d’activation fonctionnel à l’IRM lors d’une tâche de n-back. Mais le profil d’évolution diffère d’un patient à l’autre, tant sur le plan cognitif qu’à l’IRMf. Nous présenterons ici quelques études de cas.DISCUSSION : Les résultats préliminaires de l’étude PLASTIM sont en accord avec ceux observés dans les études de cas répétées de Hubacher et al. (2015) sur des patients SEP et constituent une occasion d’étudier les interactions et complémentarités entre données cognitives et IRM, notamment en terme de perception de l’efficacité de la rééducation selon le type de donnée.
Published: 2022

10. Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes

Author: Didier Auboeuf, Louison Lallemant, Cécile Martinat, Geneviève Gourdon, Julie Tahraoui-Bories, Cyril F. Bourgeois, Géraldine Sicot, Mário Gomes-Pereira, Nathalie Rouach, Hélène Polvèche, Noémie Cresto, Anchel González-Barriga, Sandra O. Braz, Oscar Hernández-Hernández, Cuauhtli N. Azotla-Vilchis, Luis E Agonizantes-Juárez, Diana M. Dincã, Laure-Elise Pillet, Aline Huguet, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Instituto Nacional de Rehabilitacion (INR), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Morphology (linguistics), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Chemistry, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Toxicity, medicine, RNA, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Adhesion, medicine.disease, Myotonic dystrophy, Cell biology
Abstract: Brain dysfunction in myotonic dystrophy type 1 (DM1), the prototype of toxic RNA disorders, has been mainly attributed to neuronal RNA misprocessing, while little attention has been given to non-neuronal brain cells. Using a transgenic mouse model of DM1 that expresses mutant RNA in various brain cell types, we demonstrate that astrocytes exhibit impaired ramification and polarization in vivo and defects in adhesion, spreading and migration. RNA-dependent toxicity and phenotypes was also found in human transfected glial cells. In line with the cell phenotypes, molecular analyses revealed extensive expression and accumulation of toxic RNA in astrocytes, which resulted in RNA spliceopathy that was remarkably more severe than in neurons. Astrocyte missplicing affected primarily transcripts that regulate cell adhesion, cytoskeleton and morphogenesis, and it was confirmed in human brain tissue. We demonstrate for the first time that DM1 impacts astrocyte cell biology, possibly compromising their support and regulation of synaptic function.
Published: 2022

11. Propagation of Distinct α-Synuclein Strains Within Human Reconstructed Neuronal Network and Associated Neuronal Dysfunctions

Author: Simona Gribaudo, Luc Bousset, Josquin Courte, Ronald Melki, Jean-Michel Peyrin, Anselme L. Perrier, Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), and Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon
Subjects: [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract: International audience; Abstract Cell motility is critical for tumor malignancy. Metabolism being an obligatory step in shaping cell behavior, we looked for metabolic weaknesses shared by motile cells across the diverse genetic contexts of patients’ glioblastoma. Computational analyses of single-cell transcriptomes from thirty patients’ tumors isolated cells with high motile potential and highlighted their metabolic specificities. These cells were characterized by enhanced mitochondrial load and oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). Functional assays with patients’ tumor-derived cells and -tissue organoids, and genetic and pharmacological manipulations confirmed that the cells depend on enhanced ROS production and MPST activity for their motility. MPST action involved protection of protein cysteine residues from damaging hyperoxidation. Its knockdown translated in reduced tumor burden, and a robust increase in mice survival. Starting from cell-by-cell analyses of the patients’ tumors, our work unravels metabolic dependencies of cell malignancy maintained across heterogeneous genomic landscapes.
Published: 2022

12. Astrocytes réactifs et maladies cérébrales: Biomarqueurs et cibles thérapeutiques

Author: Poulot-Becq-Giraudon, Yiannis, Carrillo-de Sauvage, Maria-Angeles, Escartin, Carole, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; Les astrocytes sont des partenaires essentiels des neurones dans le système nerveux central. En réponse à de nombreuses maladies qui touchent le cerveau, les astrocytes subissent des modifications morphologiques, moléculaires et fonctionnelles : ils deviennent réactifs. Ces changements multiples sont susceptibles d’avoir un impact important sur les neurones, qui dépendent de nombreuses fonctions remplies par les astrocytes. La réponse de réactivité astrocytaire dépend du contexte pathologique. Il est donc indispensable de définir précisément les changements qui se produisent dans les astrocytes réactifs dans chaque situation pathologique, par des approches adaptées et sélectives. Cela permettra le développement de thérapies innovantes ciblant ces cellules partenaires des neurones, ainsi que l’identification de biomarqueurs spécifiques de certaines maladies cérébrales.
Published: 2022

13. Human pericytes degrade diverse α-synuclein aggregates

Author: Birger Victor Dieriks, Blake Highet, Ania Alik, Tracy Bellande, Taylor J. Stevenson, Victoria Low, Thomas I-H Park, Jason Correia, Patrick Schweder, Richard L. M. Faull, Ronald Melki, Maurice A. Curtis, Mike Dragunow, University of Auckland [Auckland], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Auckland City Hospital, ANR-17-JPCD-0005,Protest-70,Protecting protein homeostasis in synucleinopathies and tauopathies by modulating the Hsp70/co-chaperone network(2017), and ANR-17-JPCD-0002,TransPathND,Intraneuronal transport-related pathways across neurodegenerative diseases(2017)
Subjects: Lewy Body Disease, Neurons, Multidisciplinary, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, alpha-Synuclein, Humans, Parkinson Disease, Pericytes
Abstract: International audience; Parkinson's disease (PD) is a progressive, neurodegenerative disorder characterised by the abnormal accumulation of α-synuclein (α-syn) aggregates. Central to disease progression is the gradual spread of pathological α-syn. α-syn aggregation is closely linked to progressive neuron loss. As such, clearance of α-syn aggregates may slow the progression of PD and lead to less severe symptoms. Evidence is increasing that non-neuronal cells play a role in PD and other synucleinopathies such as Lewy body dementia and multiple system atrophy. Our previous work has shown that pericytes-vascular mural cells that regulate the blood-brain barrier-contain α-syn aggregates in human PD brains. Here, we demonstrate that pericytes efficiently internalise fibrillar α-syn irrespective of being in a monoculture or mixed neuronal cell culture. Pericytes cleave fibrillar α-syn aggregates (Fibrils, Ribbons, fibrils65, fibrils91 and fibrils110), with cleaved α-syn remaining present for up to 21 days. The number of α-syn aggregates/cell and average aggregate size depends on the type of strain, but differences disappear within 5 five hours of treatment. Our results highlight the role brain vasculature may play in reducing α-syn aggregate burden in PD.
Published: 2022

14. Pathological changes induced by Alzheimer’s brain inoculation in amyloid-beta plaque-bearing mice

Author: Lam, Suzanne, Hérard, Anne-Sophie, Boluda, Susana, Petit, Fanny, Eddarkaoui, Sabiha, Cambon, Karine, Letournel, Franck, Martin-Négrier, Marie-Laure, Faisant, Maxime, Godfraind, Catherine, Boutonnat, Jean, Maurage, Claude-Alain, Deramecourt, Vincent, Duchesne, Mathilde, Meyronet, David, Fenouil, Tanguy, de Paula, André Mauès, Rigau, Valérie, Vandenbos-Burel, Fanny, Seilhean, Danielle, Duyckaerts, Charles, Plu, Isabelle, Chiforeanu, Dan Christian, Laquerrière, Annie, Marguet, Florent, Lannes, Béatrice, Lhermitte, Benoît, Picq, Jean-Luc, Buée, Luc, Haïk, Stéphane, Dhenain, Marc, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Mice, Cellular and Molecular Neuroscience, Amyloid beta-Peptides, Alzheimer Disease, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Animals, Brain, Humans, Neurofibrillary Tangles, Plaque, Amyloid, tau Proteins, Neurology (clinical), Pathology and Forensic Medicine
Abstract: Alzheimer's disease (AD) is characterized by intracerebral accumulations of extracellular amyloid-β (Aβ) plaques and intracellular tau pathology that spread in the brain. Three types of tau lesions occur in the form of neuropil threads, neurofibrillary tangles, and neuritic plaques i.e. tau aggregates within neurites surrounding Aβ deposits. The cascade of events linking these lesions and synaptic or memory impairments are still debated. Intracerebral infusion of human AD brain extracts in Aβ plaque-bearing mice that do not overexpress pathological tau proteins induces tau pathologies following heterotopic seeding of mouse tau protein. There is however little information regarding the downstream events including synaptic or cognitive repercussions of tau pathology induction in these models. In the present study, human AD brain extracts (ADbe) and control-brain extracts (Ctrlbe) were infused into the hippocampus of Aβ plaque-bearing APPswe/PS1dE9 mice. Memory, synaptic density, as well as Aβ plaque and tau aggregate loads, microgliosis, astrogliosis at the inoculation site and in connected regions (perirhinal/entorhinal cortex) were evaluated 4 and 8 months post-inoculation. ADbe inoculation produced the following effects: (i) memory deficit; (ii) increased Aβ plaque deposition in proximity to the inoculation site; (iii) tau pathology induction; (iv) appearance of neuropil threads and neurofibrillary tangles next to the inoculation site with a spreading to connected regions. Neuritic plaque pathology was detected in both ADbe- and Ctrlbe-inoculated animals but ADbe inoculation increased the severity close to and at distance of the inoculation site. (v) Finally, ADbe inoculation reduced synaptic density in the vicinity to the inoculation site and in connected regions as the perirhinal/entorhinal cortex. Synaptic impairments were correlated with increased severity of neuritic plaques but not to other tau lesions or Aβ lesions, suggesting that neuritic plaques are a culprit for synaptic loss. Synaptic density was also associated with microglial load. Graphical abstract
Published: 2022

15. Mesoscale connections and gene expression empower whole-brain modeling of α-synuclein spread, aggregation, and decay dynamics

Author: Ehsan Dadgar-Kiani, Gregor Bieri, Ronald Melki, Aaron D. Gitler, Jin Hyung Lee, Department of Neurology and Neurological Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Department of Bioengineering [Stanford], Stanford University, Department of Genetics [Stanford], Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Chan Zuckerberg BioHub [San Francisco, CA], Department of Neurobiology [Stanford], Department of Electrical Engineering [Stanford], and Department of Neurosurgery [Stanford]
Subjects: Synucleinopathies, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, alpha-Synuclein, Disease Progression, Humans, Brain, Gene Expression, General Biochemistry, Genetics and Molecular Biology
Abstract: International audience; An emerging view regarding neurodegenerative diseases is that discreet seeding of misfolded proteins leads to widespread pathology. However, the mechanisms by which misfolded proteins seed distinct brain regions and cause differential whole-brain pathology remain elusive. We used whole-brain tissue clearing and highresolution imaging to longitudinally map pathology in an a-synuclein pre-formed fibril injection model of Parkinson’s disease. Cleared brains at different time points of disease progression were quantitatively segmented and registered to a standardized atlas, revealing distinct phases of spreading and decline. We then fit a computational model with parameters that represent a-synuclein pathology spreading, aggregation, decay, and gene expression pattern to this longitudinal dataset. Remarkably, our model can generalize to predicting a-synuclein spreading patterns from several distinct brain regions and can even estimate their origins. This model empowers mechanistic understanding and accurate prediction of disease progression, paving the way for the development and testing of therapeutic interventions.
Published: 2022

16. Genomic evidence for global ocean plankton biogeography shaped by large-scale current systems

Author: Richter, Daniel J., Watteaux, Romain, Vannier, Thomas, Leconte, Jade, Frémont, Paul, Reygondeau, Gabriel, Maillet, Nicolas, Henry, Nicolas, Benoit, Gaëtan, da Silva, Ophélie, Delmont, Tom O., Fernández-Guerra, Antonio, Suweis, Samir, Narci, Romain, Berney, Cedric, Eveillard, Damien, Gavory, Frederick, Guidi, Lionel, Labadie, Karine, Mahieu, Eric, Poulain, Julie, Romac, Sarah, Roux, Simon, Dimier, Céline, Kandels‐Lewis, Stefanie, Picheral, Marc, Searson, Sarah, Oceans, Tara, Pesant, Stéphane, Aury, Jean-Marc, Brum, Jennifer R., Lemaitre, Claire, Pelletier, Eric, Bork, Peer, Sunagawa, Shinichi, Lombard, Fabien, Karp-Boss, Lee, Bowler, Chris, Sullivan, Matthew B., Karsenti, Eric, Mariadassou, Mahendra, Probert, Ian, Peterlongo, Pierre, Wincker, Patrick, Vargas, Colomban de, Ribera d’Alcalà, Maurizio, Iudicone, Daniele, Jaillon, Olivier, Tara Oceans Coordinators, Centre National de la Recherche Scientifique (France), European Molecular Biology Laboratory, Centre National de Séquençage (France), National Fund for Scientific Research (Belgium), Stazione Zoologica Anton Dohrn, Università degli Studi di Milano, Université Paris Sciences & Lettres, Agence Nationale de la Recherche (France), National Science Foundation (US), Veolia Foundation, Région Bretagne, World Courier, Illumina, Cap L’Orient, Fondation EDF, Fondation pour la Recherche sur la Biodiversité, Fondation Prince Albert II de Monaco, Ministère de l'Europe et des Affaires étrangères (France), Adaptation et diversité en milieu marin (ADMM), Institut national des sciences de l'Univers (INSU - CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Stazione Zoologica Anton Dohrn (SZN), Institut méditerranéen d'océanologie (MIO), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), University of British Columbia (UBC), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Max Planck Institute for Marine Microbiology, Max-Planck-Gesellschaft, Dipartimento di Fisica e Astronomia 'Galileo Galilei', Università degli Studi di Padova = University of Padua (Unipd), Consorzio Nazionale Interuniversitario per le Scienze FIsiche della Materia (CNISM), Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Sciences du Numérique de Nantes (LS2N), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Combinatoire et Bioinformatique (LS2N - équipe COMBI), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Laboratoire d'océanographie de Villefranche (LOV), Institut national des sciences de l'Univers (INSU - CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de la Mer de Villefranche (IMEV), Institut de Biologie François JACOB (JACOB), Ohio State University [Columbus] (OSU), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Marine Environmental Sciences [Bremen] (MARUM), Universität Bremen, Ecology and Evolutionary Biology [Tucson] (EEB), University of Arizona, Scalable, Optimized and Parallel Algorithms for Genomics (GenScale), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), European Molecular Biology Laboratory [Heidelberg] (EMBL), University of Maine, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Fédération de recherche de Roscoff (FR2424), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), French National Research Agency (ANR)HYDROGEN/ANR-14CE23-0001, National Science Foundation (NSF)OCE-1536989, OCE-1829831, Commissariat a l'Energie Atomique et aux Energies Alternatives, Graphene Flagship, European Project: 634486,H2020,H2020-BG-2014-2,INMARE(2015), European Project: 287589,EC:FP7:KBBE,FP7-OCEAN-2011,MICRO B3(2012), Adaptation et diversité en milieu marin (AD2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Universita degli Studi di Padova, Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Combinatoire et Bioinformatique (COMBI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Centre de Mathématiques et de Leurs Applications (CMLA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Toulon (UTLN)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Infectiologie Santé Publique (ISP-311), Institut National de la Recherche Agronomique (INRA)-Université de Tours, Institut Pprime (PPRIME), Université de Poitiers-ENSMA-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA), Laboratoire d'Informatique de Nantes Atlantique (LINA), Mines Nantes (Mines Nantes)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1)
Subjects: 010504 meteorology & atmospheric sciences, Biogeography, Oceans and Seas, Context (language use), 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, plankton biogeography, genomics, Ecosystem, genetics, 14. Life underwater, microbial oceanography, 030304 developmental biology, 0105 earth and related environmental sciences, Seascape, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, 0303 health sciences, metagenomics, General Immunology and Microbiology, Geography, General Neuroscience, Ocean current, fungi, Community structure, General Medicine, 15. Life on land, Plankton, Oceanography, 13. Climate action, Metagenomics, metabarcoding, ecology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: Biogeographical studies have traditionally focused on readily visible organisms, but recent technological advances are enabling analyses of the large-scale distribution of microscopic organisms, whose biogeographical patterns have long been debated. Here we assessed the global structure of plankton geography and its relation to the biological, chemical, and physical context of the ocean (the ‘seascape’) by analyzing metagenomes of plankton communities sampled across oceans during the Tara Oceans expedition, in light of environmental data and ocean current transport. Using a consistent approach across organismal sizes that provides unprecedented resolution to measure changes in genomic composition between communities, we report a pan-ocean, size-dependent plankton biogeography overlying regional heterogeneity. We found robust evidence for a basin-scale impact of transport by ocean currents on plankton biogeography, and on a characteristic timescale of community dynamics going beyond simple seasonality or life history transitions of plankton., We thank the commitment of the following people and sponsors who made this expedition possible: CNRS (in particular Groupement de Recherche GDR3280), European Molecular Biology Laboratory (EMBL), Genoscope/CEA, Fund for Scientific Research – Flanders, VIB, Stazione Zoologica Anton Dohrn, UNIMIB, Paris Sciences et Lettres (PSL) Research University (ANR-11-IDEX-0001–02), the French Government ANR (projects FRANCE GENOMIQUE/ANR-10-INBS-09, MEMO LIFE/ANR-10-LABX-54, POSEIDON/ANR-09-BLAN-0348, PROMETHEUS/ANR-09-PCS-GENM-217, MAPPI/ANR-2010-COSI-004, TARA-GIRUS/ANR-09-PCS-GENM-218), US NSF grant DEB-1031049, FWO, BIO5, Biosphere 2, Agnès b., the Veolia Environment Foundation, Région Bretagne, World Courier, Illumina, Cap L’Orient, the EDF Foundation EDF Diversiterre, FRB, the Prince Albert II de Monaco Foundation, Etienne Bourgois, the Tara schooner and its captain and crew. We thank MERCATOR-CORIOLIS and ACRI-ST for providing daily satellite data during the expedition. The bulk of genomic computations were performed using the Airain HPC machine provided through GENCI- [TGCC/CINES/IDRIS] (grants t2011076389, t2012076389, t2013036389, t2014036389, t2015036389 and t2016036389). We are also grateful to the French Ministry of Foreign Affairs for supporting the expedition and to the countries who granted us sampling permissions.
Published: 2022

17. Rééducation de la mémoire de travail après une lésion cérébrale acquise: Etude cognitive et IRM (PLASTIM-MDTC): Résultats préliminaires : 2 études de cas

Author: Mazo, Guillaume, Michel Pantaléo, Stéphanie, Picq, Jean-Luc, Hertz-Pannier, Lucie, Brunet-Gouet, Eric, Azouvi, Philippe, Vallat-Azouvi, Claire, Université Paris 8 Vincennes-Saint-Denis - UFR de psychologie, Université Paris 8 Vincennes-Saint-Denis (UP8), Fonctionnement et Dysfonctionnement Cognitifs : Les âges de la vie (DysCo), Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN), Antenne UEROS-UGECAMIDF - Hôpital Raymond Poincarré [Garches], Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), CEA, NeuroSpin UNIACT, Épilepsie de l'enfant et plasticité cérébrale (Inserm U1129), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Raymond Poincaré [AP-HP], Journées de Printemps de la SNLF, Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB)
Subjects: [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SCCO.PSYC]Cognitive science/Psychology, [SHS.PSY]Humanities and Social Sciences/Psychology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract: International audience
Published: 2022

18. Modelling $\alpha$-synuclein aggregation and neurodegeneration with fibril seeds in primary cultures of mouse dopaminergic neurons

Author: Aurore Tourville, David Akbar, Olga Corti, Jochen H. M. Prehn, Ronald Melki, Stéphane Hunot, Patrick P. Michel, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Royal College of Surgeons in Ireland (RCSI), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Association France Parkinson (DOXYPARK), program Investissements d’Avenir [ANR-10-IAIHU-06], ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), European Project: 821522,PD-MitoQUANT - H2020-EU.3.1.7. - Innovative Medicines Initiative 2 (IMI2), Melki, Ronald, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, A quantitative approach towards the characterisation of mitochondrial dysfunction in Parkinson's disease - PD-MitoQUANT - H2020-EU.3.1.7. - Innovative Medicines Initiative 2 (IMI2) - 821522 - INCOMING, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), ANR-10-IAIHU-0006, and Michel, Patrick Pierre
Subjects: α-Synuclein, Dopamine, Dopaminergic Neurons, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, neurodegeneration, General Medicine, dopamine neurons, cell culture model, protein aggregation, Parkinson disease, Mice, nervous system, $\alpha$-Synuclein, Mesencephalon, alpha-Synuclein, Animals, fibril seeds
Abstract: International audience; To model $\alpha$-Synuclein ($\alpha$S) aggregation and neurodegeneration in Parkinson's disease (PD), we established cultures of mouse midbrain dopamine (DA) neurons and chronically exposed them to fibrils 91 (F91) generated from recombinant human $\alpha$S. We found that F91 have an exquisite propensity to seed the aggregation of endogenous $\alpha$S in DA neurons when compared to other neurons in midbrain cultures. Until two weeks post-exposure, somal aggregation in DA neurons increased with F91 concentrations (0.01-0.75 μM) and the time elapsed since the initiation of seeding, with, however, no evidence of DA cell loss within this time interval. Neither toxin-induced mitochondrial deficits nor genetically induced loss of mitochondrial quality control mechanisms promoted F91-mediated $\alpha$S aggregation or neurodegeneration under these conditions. Yet, a significant loss of DA neurons (~30%) was detectable three weeks after exposure to F91 (0.5 μM), i.e., at a time point where somal aggregation reached a plateau. This loss was preceded by early deficits in DA uptake. Unlike $\alpha$S aggregation, the loss of DA neurons was prevented by treatment with GDNF, suggesting that αS aggregation in DA neurons may induce a form of cell death mimicking a state of trophic factor deprivation. Overall, our model system may be useful for exploring PD-related pathomechanisms and for testing molecules of therapeutic interest for this disorder.
Published: 2022

19. An evolutionary gap in primate default mode network organization

Author: Clément M. Garin, Yuki Hori, Stefan Everling, Christopher T. Whitlow, Finnegan J. Calabro, Beatriz Luna, Mathilda Froesel, Maëva Gacoin, Suliann Ben Hamed, Marc Dhenain, Christos Constantinidis, The University of Western Ontario, Instituto de Fisica (IF), Universidad Autonoma de San Luis Potosi [México] (UASLP), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Department of Neurobiology and Anatomy, and Wake Forest University
Subjects: Brain Mapping, marmoset, mouse lemur, Neuroscience [CP], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SCCO.NEUR]Cognitive science/Neuroscience, primates, fMRI, macaque, Brain, Default Mode Network, Callithrix, Magnetic Resonance Imaging, General Biochemistry, Genetics and Molecular Biology, resting-state, Neural Pathways, evolution, Animals, DMN, medial prefrontal cortex, BOLD
Abstract: The human default mode network (DMN) is engaged at rest and in cognitive states such as self-directed thoughts. Interconnected homologous cortical areas in primates constitute a network considered as the equivalent. Here, based on a cross-species comparison of the DMN between humans and non-hominoid primates (macaques, marmosets, and mouse lemurs), we report major dissimilarities in connectivity profiles. Most importantly, the medial prefrontal cortex (mPFC) of non-hominoid primates is poorly engaged with the posterior cingulate cortex (PCC), though strong correlated activity between the human PCC and the mPFC is a key feature of the human DMN. Instead, a fronto-temporal resting-state network involving the mPFC was detected consistently across non-hominoid primate species. These common functional features shared between non-hominoid primates but not with humans suggest a substantial gap in the organization of the primate's DMN and its associated cognitive functions.
Published: 2022

20. Pharmacokinetic neuroimaging to study the dose-related brain kinetics and target engagement of buprenorphine in vivo

Author: Matteo Tonietto, Catriona Wimberley, Sébastien Goutal, Sylvain Auvity, Dominique Vodovar, Fabien Caillé, Alain Pruvost, Nicolas Tournier, Michel Bottlaender, Claire Leroy, Unité BioMaps (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Queen's Medical Researche Institute, University of Edinburgh, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Tournier, Nicolas
Subjects: Narcotic Antagonists, [SDV]Life Sciences [q-bio], Analgesic, Neuroimaging, (+)-Naloxone, Pharmacology, Article, 03 medical and health sciences, 0302 clinical medicine, MicroDose, Naltrindole, Animals, Medicine, business.industry, Antagonist, Brain, Binding potential, Buprenorphine, Rats, 3. Good health, 030227 psychiatry, [SDV] Life Sciences [q-bio], Kinetics, Psychiatry and Mental health, business, Norbinaltorphimine, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; A wide range of buprenorphine doses are used for either pain management or maintenance therapy in opioid addiction. The complex in vitro profile of buprenorphine, with affinity for µ-, δ-, and κ-opioid receptors (OR), makes it difficult to predict its dose-related neuropharmacology in vivo. In rats, microPET imaging and pretreatment by OR antagonists were performed to assess the binding of radiolabeled buprenorphine (microdose 11C-buprenorphine) to OR subtypes in vivo (n = 4 per condition). The µ-selective antagonist naloxonazine (10 mg/kg) and the non-selective OR antagonist naloxone (1 mg/kg) blocked the binding of 11C-buprenorphine, while pretreatment by the δ-selective (naltrindole, 3 mg/kg) or the κ-selective antagonist (norbinaltorphimine, 10 mg/kg) did not. In four macaques, PET imaging and kinetic modeling enabled description of the regional brain kinetics of 11C-buprenorphine, co-injected with increasing doses of unlabeled buprenorphine. No saturation of the brain penetration of buprenorphine was observed for doses up to 0.11 mg/kg. Regional differences in buprenorphine-associated receptor occupancy were observed. Analgesic doses of buprenorphine (0.003 and 0.006 mg/kg), respectively, occupied 20% and 49% of receptors in the thalamus while saturating the low but significant binding observed in cerebellum and occipital cortex. Occupancy >90% was achieved in most brain regions with plasma concentrations >7 µg/L. PET data obtained after co-injection of an analgesic dose of buprenorphine (0.003 mg/kg) predicted the binding potential of microdose 11C-buprenorphine. This strategy could be further combined with pharmacodynamic exploration or pharmacological MRI to investigate the neuropharmacokinetics and neuroreceptor correlate, at least at µ-OR, of the acute effects of buprenorphine in humans.
Published: 2021

21. De nouvelles techniques pour dévoiler le rôle des cellules gliales du cerveau

Author: Hélène Hirbec, Carole Escartin, Lucile Ben Haim, Anne-Laure Hemonnot-Girard, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Sciences, EDP, Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: [SDV] Life Sciences [q-bio], 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, [SDV]Life Sciences [q-bio], Philosophy, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], General Medicine, Humanities, 030217 neurology & neurosurgery, General Biochemistry, Genetics and Molecular Biology, 030304 developmental biology
Abstract: Brain function relies on complex interactions between neurons and different types of glial cells, such as astrocytes, microglia and oligodendrocytes. The relatively young field of "gliobiology" is thriving. Thanks to various technical innovations, it is now possible to address challenging biological questions on glial cells and unravel their multiple roles in brain function and dysfunction., L’exécution des fonctions cérébrales requiert des interactions optimales entre les neurones et les différents types de cellules gliales (astrocytes, microglies et oligodendrocytes). Le domaine de la gliobiologie, qui s’intéresse aux cellules gliales, est en pleine expansion. Les innovations techniques permettent désormais d’aborder des questions biologiques complexes quant aux rôles de ces cellules dans le fonctionnement physiologique et pathologique du cerveau. Dans cette synthèse, nous décrivons comment certaines de ces avancées techniques nous ont permis d’en apprendre davantage sur les origines et les rôles fonctionnels des cellules gliales. Nous illustrons également comment ces techniques et les découvertes qui en ont découlé, peuvent être transposées en clinique et pourraient, dans un futur proche, offrir des nouvelles perspectives thérapeutiques.
Published: 2021

22. Increased microglial activation in patients with Parkinson disease using [18F]-DPA714 TSPO PET imaging

Author: Marie Sarazin, Philippe Gervais, Matteo Tonietto, Julien Lagarde, Sonia Lavisse, Marie-Anne Peyronneau, Philippe Hantraye, Claire Thiriez, Philippe Remy, Catriona Wimberley, Olivier Barret, Sébastien Goutal, Michel Bottlaender, Bertrand Kuhnast, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unité BioMaps (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche en NeuroImagerie Applicative Clinique et Translationnelle (UNIACT), Service NEUROSPIN (NEUROSPIN), Université Paris Cité (UPCité), GHU Paris Psychiatrie et Neurosciences, Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor, This work was supported by France Parkinson (GAO 2008), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), CHU Henri Mondor [Créteil], Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP), CCSD, Accord Elsevier, and Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Disease, 03 medical and health sciences, 0302 clinical medicine, Neuroinflammation, In vivo, Internal medicine, Post-hoc analysis, Medicine, Dopamine transporter, Microglia, biology, business.industry, Neurodegeneration, medicine.disease, [SDV] Life Sciences [q-bio], Parkinson disease, PET, 030104 developmental biology, medicine.anatomical_structure, TSPO[$^{18}$F]-DPA714, Neurology, biology.protein, [(18)F]-DPA714, Neurology (clinical), Analysis of variance, Geriatrics and Gerontology, business, TSPO, 030217 neurology & neurosurgery
Abstract: International audience; Introduction: Increasing evidence suggests that neuroinflammation is active in Parkinson disease (PD) and contributes to neurodegeneration. This process can be studied in vivo with PET and radioligands targeting TSPO, upregulated in activated microglia. Initial PET studies investigating microglial activation in PD with the [11C]-PK11195 have provided inconclusive results. Here we assess the presence and distribution of neuroinflammatory response in PD patients using [18F]-DPA714 and to correlate imaging biomarkers to dopamine transporter imaging and clinical status.Methods: PD patients (n = 24, Hoehn and Yahr I-III) and 28 healthy controls were scanned with [18F]-DPA714 and [11C]-PE2I and analyzed. They were all genotyped for TSPO polymorphism. Regional binding parameters were estimated (reference Logan graphical approach with supervised cluster analysis). Impact of TSPO genotype was analyzed using Wilcoxon signed-rank test. Differences between groups were investigated using a two-way ANOVA and Tukey post hoc tests.Results: PD patients showed significantly higher [18F]-DPA714 binding compared to healthy controls bilaterally in the midbrain (p < 0.001), the frontal cortex (p = 0.001), and the putamen contralateral to the more clinically affected hemibody (p = 0.038). Microglial activation in these regions did not correlate with the severity of motor symptoms, disease duration nor putaminal [11C]-PE2I uptake. However, there was a trend toward a correlation between cortical TSPO binding and disease duration (p = 0.015 uncorrected, p = 0.07 after Bonferroni correction).Conclusion: [18F]-DPA714 binding confirmed that there is a specific topographic pattern of microglial activation in the nigro-striatal pathway and the frontal cortex of PD patients.Trial registration: Trial registration: INFLAPARK, NCT02319382. Registered 18 December 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02319382.
Published: 2021

23. STAT3-Mediated Astrocyte Reactivity Associated with Brain Metastasis Contributes to Neurovascular Dysfunction

Author: Manuel Sarmiento Soto, Alexandre A. Khrapitchev, Chris Martin, James R. Larkin, Gilles Bonvento, Sébastien Serres, Helen Scott, Carole Escartin, Vasiliki Economopoulos, Melissa Maczka, Nicola R. Sibson, University of Oxford, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), University of Nottingham, UK (UON), University of Oxford [Oxford], Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Cancer Research UK, Brain Tumour Charity, and European Union (UE). H2020
Subjects: STAT3 Transcription Factor, 0301 basic medicine, Cancer Research, Magnetic Resonance Spectroscopy, Pyridines, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Ciliary neurotrophic factor, Multimodal Imaging, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Humans, Ciliary Neurotrophic Factor, STAT3, biology, Brain Neoplasms, business.industry, Rats, Inbred Strains, Neoplasms, Experimental, Human brain, Tyrphostins, medicine.disease, Rats, Laser Speckle Contrast Imaging, 030104 developmental biology, medicine.anatomical_structure, Oncology, Cerebral blood flow, Astrocytes, Cerebrovascular Circulation, 030220 oncology & carcinogenesis, biology.protein, Immunohistochemistry, Female, business, Neuroscience, Brain metastasis, Astrocyte
Abstract: Astrocytes are thought to play a pivotal role in coupling neural activity and cerebral blood flow. However, it has been shown that astrocytes undergo morphologic changes in response to brain metastasis, switching to a reactive phenotype, which has the potential to significantly compromise cerebrovascular function and contribute to the neurological sequelae associated with brain metastasis. Given that STAT3 is a key regulator of astrocyte reactivity, we aimed here to determine the impact of STAT3-mediated astrocyte reactivity on neurovascular function in brain metastasis. Rat models of brain metastasis and ciliary neurotrophic factor were used to induce astrocyte reactivity. Multimodal imaging, electrophysiology, and IHC were performed to determine the relationship between reactive astrocytes and changes in the cerebrovascular response to electrical and physiological stimuli. Subsequently, the STAT3 pathway in astrocytes was inhibited with WP1066 to determine the role of STAT3-mediated astrocyte reactivity, specifically, in brain metastasis. Astrocyte reactivity associated with brain metastases impaired cerebrovascular responses to stimuli at both the cellular and functional level and disrupted astrocyte–endothelial interactions in both animal models and human brain metastasis samples. Inhibition of STAT3-mediated astrocyte reactivity in rats with brain metastases restored cerebrovascular function, as shown by in vivo imaging, and limited cerebrovascular changes associated with tumor growth. Together these findings suggest that inhibiting STAT3-mediated astrocyte reactivity may confer significant improvements in neurological outcome for patients with brain metastases and could potentially be tested in other brain tumors. Significance: These findings demonstrate that selectively targeting STAT3-mediated astrocyte reactivity ameliorates the cerebrovascular dysfunction associated with brain metastasis, providing a potential therapeutic avenue for improved patient outcome.
Published: 2020

24. Lean regional muscle volume estimates using explanatory bioelectrical models in healthy subjects and patients with muscle wasting

Author: Bachasson, Damien, Carras Ayaz, Alper, Mosso, Jessie, Canal, Aurélie, Boisserie, Jean-Marc, Araujo, Ericky, Benveniste, Olivier, Reyngoudt, Harmen, Marty, Benjamin, Carlier, Pierre, Hogrel, Jean-Yves, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Gestionnaire, Hal Sorbonne Université, Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), CHU Pitié-Salpêtrière [AP-HP], Centre de Recherche en Myologie, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP]
Subjects: Bioelectrical impedance analysis, lcsh:Diseases of the musculoskeletal system, Muscle volume, [SDV]Life Sciences [q-bio], Skeletal muscle, Reproducibility of Results, Muscle mass, lcsh:Human anatomy, Original Articles, Healthy Volunteers, lcsh:QM1-695, [SDV] Life Sciences [q-bio], Body Composition, Electric Impedance, Humans, Original Article, Myopathies, Muscle atrophy, lcsh:RC925-935, Muscle fatty infiltration, Muscle, Skeletal
Abstract: International audience; Background: The availability of non-invasive, accessible, and reliable methods for estimating regional skeletal muscle volume is paramount in conditions involving primary and/or secondary muscle wasting. This work aimed at (i) optimizing serial bioelectrical impedance analysis (SBIA ) by computing a conductivity constant based on quantitative magnetic resonance imaging (MRI) data and (ii) investigating the potential of SBIA for estimating lean regional thigh muscle volume in patients with severe muscle disorders.Methods: Twenty healthy participants with variable body mass index and 20 patients with idiopathic inflammatory myopathies underwent quantitative MRI. Anatomical images and fat fraction maps were acquired in thighs. After manual muscle segmentation, lean thigh muscle volume (lVMRI ) was computed. Subsequently, multifrequency (50 to 350 kHz) serial resistance profiles were acquired between current skin electrodes (i.e. ankle and hand) and voltage electrodes placed on the anterior thigh. In vivo values of the muscle electrical conductivity constant were computed using data from SBIA and MRI gathered in the right thigh of 10 healthy participants. Lean muscle volume (lVBIA ) was derived from SBIA measurements using this newly computed constant. Between-day reproducibility of lVBIA was studied in six healthy participants.Results: Electrical conductivity constant values ranged from 0.82 S/m at 50 kHz to 1.16 S/m at 350 kHz. The absolute percentage difference between lVBIA and lVMRI was greater at frequencies >270 kHz (P < 0.0001). The standard error of measurement and the intra-class correlation coefficient for lVBIA computed from measurements performed at 155 kHz (i.e. frequency with minimal difference) against lVMRI were 6.1% and 0.95 in healthy participants and 9.4% and 0.93 in patients, respectively. Between-day reproducibility of lVBIA was as follows: standard error of measurement = 4.6% (95% confidence interval [3.2, 7.8] %), intra-class correlation coefficient = 0.98 (95% confidence interval [0.95, 0.99]).Conclusions: These findings demonstrate a strong agreement of lean muscle volume estimated using SBIA against quantitative MRI in humans, including in patients with severe muscle wasting and fatty degeneration. SBIA shows promises for non-invasive, fast, and accessible estimation and follow-up of lean regional skeletal muscle volume for transversal and longitudinal studies.
Published: 2020

25. Neurons with Cat's Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

Author: Francesca De Giorgi, Muhammed Bilal Abdul-Shukkoor, Marianna Kashyrina, Leslie-Ann Largitte, Francesco De Nuccio, Brice Kauffmann, Alons Lends, Florent Laferrière, Sébastien Bonhommeau, Dario Domenico Lofrumento, Luc Bousset, Erwan Bezard, Thierry Buffeteau, Antoine Loquet, François Ichas, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Salento [Lecce], Soutien à la Recherche de l'Institut Européen de Chimie Biologique, Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Européen de Chimie et de Biologie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1 (UB)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), ANR-20-CE29-0004,AQUATERS,Imagerie structurale et morphologique nanométrique d'agrégats bêta amyloïdes interagissant avec des membranes en milieu aqueux(2020), Ichas, Francois, and Université Paris-Saclay-Institut de Biologie François JACOB (JACOB)
Subjects: Amyloid, Synucleinopathies, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Intranuclear Inclusion Bodies, α-Synuclein, amyloid, fibril, strain, neuron, nuclear, inclusion, lentiform, cat eye, Multiple System Atrophy, Parkinson’s disease, Biochemistry, Mice, Animals, Molecular Biology, Neurons, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, nervous system diseases, [SDV] Life Sciences [q-bio], nervous system, alpha-Synuclein
Abstract: The distinct neuropathological features of the different α-Synucleinopathies, as well as the diversity of the α-Synuclein (α-Syn) intracellular inclusion bodies observed in post mortem brain sections, are thought to reflect the strain diversity characterizing invasive α-Syn amyloids. However, this “one strain, one disease” view is still hypothetical, and to date, a possible disease-specific contribution of non-amyloid factors has not been ruled out. In Multiple System Atrophy (MSA), the buildup of α-Syn inclusions in oligodendrocytes seems to result from the terminal storage of α-Syn amyloid aggregates first pre-assembled in neurons. This assembly occurs at the level of neuronal cytoplasmic inclusions, and even earlier, within neuronal intranuclear inclusions (NIIs). Intriguingly, α-Syn NIIs are never observed in α-Synucleinopathies other than MSA, suggesting that these inclusions originate (i) from the unique molecular properties of the α-Syn fibril strains encountered in this disease, or alternatively, (ii) from other factors specifically dysregulated in MSA and driving the intranuclear fibrillization of α-Syn. We report the isolation and structural characterization of a synthetic human α-Syn fibril strain uniquely capable of seeding α-Syn fibrillization inside the nuclear compartment. In primary mouse cortical neurons, this strain provokes the buildup of NIIs with a remarkable morphology reminiscent of cat’s eye marbles (see video abstract). These α-Syn inclusions form giant patterns made of one, two, or three lentiform beams that span the whole intranuclear volume, pushing apart the chromatin. The input fibrils are no longer detectable inside the NIIs, where they become dominated by the aggregation of endogenous α-Syn. In addition to its phosphorylation at S129, α-Syn forming the NIIs acquires an epitope antibody reactivity profile that indicates its organization into fibrils, and is associated with the classical markers of α-Syn pathology p62 and ubiquitin. NIIs are also observed in vivo after intracerebral injection of the fibril strain in mice. Our data thus show that the ability to seed NIIs is a strain property that is integrally encoded in the fibril supramolecular architecture. Upstream alterations of cellular mechanisms are not required. In contrast to the lentiform TDP-43 NIIs, which are observed in certain frontotemporal dementias and which are conditional upon GRN or VCP mutations, our data support the hypothesis that the presence of α-Syn NIIs in MSA is instead purely amyloid-strain-dependent.
Published: 2022

26. Physiological synaptic activity and recognition memory require astroglial glutamine

Author: Giselle Cheung, Danijela Bataveljic, Josien Visser, Naresh Kumar, Julien Moulard, Glenn Dallérac, Daria Mozheiko, Astrid Rollenhagen, Pascal Ezan, Cédric Mongin, Oana Chever, Alexis-Pierre Bemelmans, Joachim Lübke, Isabelle Leray, Nathalie Rouach, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole doctorale Cerveau Cognition et Comportement [Paris] (ED 158 - 3C), Sorbonne Université (SU), Photophysique et Photochimie Supramoléculaires et Macromoléculaires (PPSM), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institute of Neuroscience and Medicine [Jülich] (INM-1), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry, Psychotherapy and Psychosomatics [Aachen], and Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH)
Subjects: Male, MESH: Hippocampus, Intravital Microscopy, MESH: Mice, Transgenic, Glutamine, Science, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, Glutamic Acid, MESH: Stereotaxic Techniques, General Physics and Astronomy, Mice, Transgenic, MESH: Cognition, MESH: Rhodamines, Hippocampus, Synaptic Transmission, General Biochemistry, Genetics and Molecular Biology, Stereotaxic Techniques, Mice, MESH: Intravital Microscopy, Cognition, MESH: Recognition, Psychology, MESH: Synaptic Transmission, Animals, MESH: Animals, MESH: Mice, Fluorescent Dyes, Neurons, MESH: Glutamine, Multidisciplinary, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Rhodamines, MESH: Molecular Probes, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Recognition, Psychology, MESH: Glutamic Acid, General Chemistry, MESH: Fluorescent Dyes, MESH: Male, MESH: Astrocytes, MESH: Models, Animal, Astrocytes, Molecular Probes, Models, Animal, ddc:500
Abstract: Nature Communications 13, 753 (2022). doi:10.1038/s41467-022-28331-7, Published by Nature Publishing Group UK, [London]
Published: 2022

27. Using spectrally-selective radiofrequency pulses to enhance lactate signal for diffusion-weighted MRS measurements in vivo

Author: Eloïse Mougel, Sophie Malaquin, Julien Valette, Mélissa Vincent, Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Nuclear and High Energy Physics, Materials science, Magnetic Resonance Spectroscopy, Radio Waves, Biophysics, Biochemistry, Signal, 030218 nuclear medicine & medical imaging, Diffusion, 03 medical and health sciences, Mice, 0302 clinical medicine, Nuclear magnetic resonance, In vivo, Animals, Lactic Acid, Diffusion (business), [PHYS]Physics [physics], Attenuation, Resonance, Nuclear magnetic resonance spectroscopy, Condensed Matter Physics, Magnetic Resonance Imaging, Coupling (electronics), Spin echo, 030217 neurology & neurosurgery
Abstract: International audience; Measurement of lactate diffusion properties using diffusion-weighted magnetic resonance spectroscopy in vivo may allow elucidating brain lactate cellular compartmentation, which would be of great importance for neuroscience. However, measuring lactate signal is complicated by low signal-to-noise ratio due to low lactate concentration and J-modulation of its 1.3 ppm peak. In this work, we assess the benefits of using a diffusion-weighting spin echo block and spectrally selective refocusing pulses to suppress the effect of J-coupling on the 1.3 ppm lactate resonance, by not refocusing its coupling partner at 4.1 ppm. Two different kinds of spectrally selective pulses, either polychromatic or single-band, are evaluated in the mouse brain at 11.7 T. Almost complete suppression of J-modulation is shown, resulting in an approximately twofold signal increase as compared to a reference STE-LASER sequence (for the specific diffusion times used in this work). Repeated measurements confirm that lactate diffusion-weighted signal attenuation is measured with an approximately twofold precision.
Published: 2022

28. Étude du métabolisme énergétique in vivo par IRM-CEST du glucose

Author: Mathieu-Daudé, Yohann, STAR, ABES, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Julien Valette, and Julien Flament
Subjects: Glucose, Metabolism, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Métabolisme, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, CEST, MRI, IRM
Abstract: Neurodegenerative diseases are a major societal issue and their early detection is essential to better manage patients and to consider the application of a potential treatment. One of the biomarkers for detecting the disease even before the onset of symptoms is cerebral glucose consumption. Indeed, glucose is an essential molecule for energy production and our brain is the organ which consumes the most of glucose. In order to better understand the physiopathology of these diseases, the use of animal models is particularly interesting because it allows, among other things, to study the evolution of the disease from the first months of life of the animals. However, existing imaging methods, such as positron emission tomography or autoradiography, are not suitable for longitudinal follow-up of the many existing rodent models due to their lack of spatial resolution or the need to sacrifice the animal. In order to overcome these drawbacks we developped during this thesis the Chemical Exchange Saturation Transfer (CEST) imaging of glucose with the goal of mapping the energy metabolism in vivo with a good spatial resolution. The objective of this thesis work was therefore to optimize, characterize and evaluate the potential of glucoCEST imaging for the investigation of brain metabolism in vivo. We first optimized the CEST sequence's parameters in order to be as sensitive and specific as possible to glucose and its analogs. We then answered a major question about the compartmental origin of the CEST signal by showing that it originates from both extracellular and intracellular compartments. Based on these results, we evaluated the potential of CEST imaging to monitor energy metabolism in different brain structures and then applied it to longitudinal monitoring of control rats and rats with Huntington's disease. We were thus able to observe metabolic differences between these cohorts. Finally, we worked on the quantification of the CEST signal. All these results show the applications of glucoCEST imaging as a relevant tool for monitoring cerebral energy metabolism in rodent models., Les maladies neurodégénératives sont un enjeu de société majeur et leur détection précoce est essentielle pour mieux prendre en charge les patients et pour envisager l'application d'un traitement potentiel. L'un des biomarqueurs pour détecter la maladie avant même l'apparition de symptômes est la consommation cérébrale de glucose. En effet, le glucose est une molécule essentielle à la production d'énergie et notre cerveau est l'organe de notre corps qui en consomme le plus. Afin de mieux comprendre la physiopathologie de ces maladies, le recours aux modèles animaux est particulièrement intéressant car il permet, entre autres, d'étudier l'évolution de la maladie dès les premiers mois de vie des animaux. Cependant, les méthodes d'imagerie existantes, telles que la tomographie par émission de positrons ou l'autoradiographie ne sont pas adaptées au suivi longitudinal des nombreux modèles rongeurs existants du fait de leur manque de résolution spatiale ou de la nécessité de sacrifier l'animal. Afin de pallier ces inconvénients nous avons développé au cours de cette thèse l'imagerie de Transfert de Saturation par Échange chimique (CEST) du glucose dont l'objectif était de cartographier le métabolisme énergétique in vivo avec une très bonne résolution spatiale. L'objectif de ce travail de thèse a donc été d'optimiser, caractériser et évaluer le potentiel de l'imagerie glucoCEST pour l'investigation du métabolisme cérébral in vivo. Nous avons tout d'abord optimisé les paramètres de la séquence CEST afin d'être le plus sensible et spécifique possible au glucose et à ses différents analogues. Nous avons ensuite répondu à une question majeure qui est l'origine compartimentale du signal CEST en montrant qu'il provenait des compartiments extracellulaire et intracellulaire. A partir de ces résultats nous avons évalué le potentiel de l'imagerie CEST à suivre le métabolisme énergétique dans différentes structures cérébrales puis nous l'avons appliqué au suivi longitudinal de rats contrôles et de rats atteints de la maladie de Huntington. Nous avons ainsi pu observer des différences métaboliques entre ces cohortes. Enfin, nous avons travaillé sur la quantification du signal CEST. L'ensemble de ces résultats montre les applications de l'imagerie glucoCEST comme outil pertinent du suivi du métabolisme énergétique cérébral dans les modèles rongeurs.
Published: 2022

29. Evaluation of Memantine in AAV-AD Rat: A Model of Late-Onset Alzheimer’s Disease Predementia

Author: Souchet, B., Audrain, M., Alves, S., Fol, R., Tada, S., Orefice, N.S, Potier, B., Dutar, P., Billard, Jean-Marie, Cartier, N., Braudeau, J., Billard, Jean-Marie, Université Paris Sud Orsay, Université Paris-Saclay, Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Psychiatrie et Neurosciences, UMR_S894, INSERM, Université Paris Descartes, Sorbonne Paris Cité, Paris, Mobilités : Vieillissement, Pathologie, Santé (COMETE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Centre de Psychiatrie et Neurosciences (U894), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: AAV-AD rat, Tauopathies, prevention, Alzheimer Disease, animal model, Animals, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], LOAD, memantine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Rats
Abstract: International audience; BACKGROUND: Though our understanding of Alzheimer's disease (AD) remains elusive, it is well known that the disease starts long before the first signs of dementia. This is supported by the large number of symptomatic drug failures in clinical trials and the increased trend to enroll patients at predementia stages with either mild or no cognitive symptoms. However, the design of pre-clinical studies does not follow this attitude, in particular regarding the choice of animal models, often irrelevant to mimic predementia Late Onset Alzheimer 's Disease (LOAD). OBJECTIVES: We aimed to pharmacologically validate the AAV-AD rat model to evaluate preventive treatment of AD. METHODS: We evaluated an N-methyl-D-aspartate receptor antagonist, named memantine, in AAV-AD rats, an age-dependent amyloid rat model which closely mimics Alzheimer's pathology including asymptomatic and prodromal stages. Memantine was used at a clinically relevant dose (20 mg daily oral administration) from 4 (asymptomatic phase) to 10 (mild cognitive impairment phase) months of age. RESULTS: A 6-month treatment with memantine promoted a non-amyloidogenic cleavage of APP followed by a decrease in soluble Aβ42. Consequently, both long-term potentiation and cognitive impairments were prevented. By contrast, the levels of hyperphosphorylated endogenous tau remained unchanged, indicating that a long-term memantine treatment is ineffective to restrain the APP processing-induced tauopathy. CONCLUSIONS: Together, our data confirm that relevant models to LOAD, such as the AAV-AD rat, can provide a framework for a better understanding of the disease and accurate assessment of preventive treatments.
Published: 2022

30. Distinct alpha‐Synuclein species induced by seeding are selectively cleared by the Lysosome or the Proteasome in neuronally differentiated SH‐SY5Y cells

Author: Pantazopoulou, Marina, Brembati, Viviana, Kanellidi, Angeliki, Bousset, Luc, Melki, Ronald, Stefanis, Leonidas, Leonidas, Stefanis, Biomedical Research Foundation of the Academy of Athens (BRFAA), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), European Project: (grant No 116060),IMPRiND, Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Proteasome Endopeptidase Complex, SH-SY5Y, Cell Survival, alpha-synuclein, [SDV]Life Sciences [q-bio], animal diseases, environment and public health, Biochemistry, Cell Line, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Lysosome, Autophagy, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, heterocyclic compounds, degradation, Neurons, Sirolimus, Alpha-synuclein, biology, phosphorylation, Chemistry, aggregation, Proteinase K, Immunohistochemistry, nervous system diseases, Cell biology, proteasome, 030104 developmental biology, medicine.anatomical_structure, nervous system, Proteasome, Doxycycline, lysosome, biology.protein, Phosphorylation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Lysosomes, 030217 neurology & neurosurgery, Intracellular, Signal Transduction
Abstract: Accepted Articles will appear in the future; International audience; A major pathological feature of Parkinson’s disease (PD) is the aberrant accumulation of misfolded assemblies of alpha‐synuclein (α‐Syn). Protein clearance appears as a regulator of the ‘’α‐Syn burden” underlying PD pathogenesis. The picture emerging is that a combination of pathways with complementary roles, including the Proteasome System and the Autophagy‐Lysosome Pathway, contributes to the intracellular degradation of α‐Syn. The current study addresses the mechanisms governing the degradation of α‐Syn species seeded by exogenous fibrils in neuronally differentiated SH‐SY5Y neuroblastoma cells with inducible expression of α‐Syn. Using human α‐Syn recombinant fibrils (pre‐formed fibrils, PFFs), seeding and aggregation of endogenous Proteinase K (PK)‐resistant α‐Syn species occurs within a time frame of 6 days, and is still prominent after 12 days of PFF addition. Clearance of α‐Syn assemblies in this inducible model was enhanced after switching off α‐Syn expression with doxycycline. Lysosomal inhibition led to accumulation of SDS‐soluble α‐Syn aggregates 6 days after PFF‐addition or when switching off α‐Syn expression. Additionally, the autophagic enhancer, rapamycin, induced the clearance of α‐Syn aggregates 13 days post‐PFF addition, indicating that autophagy is the major pathway for aggregated α‐Syn clearance. SDS‐soluble phosphorylated α‐Syn at S129 was only apparent at 7 days of incubation with a higher amount of PFFs. Proteasomal inhibition resulted in further accumulation of SDS‐soluble phosphorylated α‐Syn at S129, with limited PK resistance. Our data suggest that in this inducible model autophagy is mainly responsible for the degradation of fibrillar α‐Syn, whereas the Proteasome System is responsible, at least in part, for the selective clearance of phosphorylated α‐Syn oligomers.
Published: 2020

31. Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease

Author: Martine Guillermier, Carole Escartin, Océane Guillemaud, Alexis-Pierre Bemelmans, Charlène Joséphine, Gilles Bonvento, Emmanuel Brouillet, Kelly Ceyzériat, Thomas Saint-Georges, Philippe Hantraye, Maria-Angeles Carrillo-de Sauvage, Karine Cambon, Sueva Bernier, Fanny Petit, Lucile Ben Haim, Anne-Sophie Hérard, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), ANR-16-TERC-0016,DecodAstro,Decoder la complexité de la réactivité astrocytaire dans les maladies neurodégénératives(2016), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Signal Transduction, 0301 basic medicine, Aging, MESH: Hippocampus, JAK-STAT3 pathway, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Hippocampal formation, MESH: Janus Kinase 2, 0302 clinical medicine, Neuroinflammation, MESH: Animals, SOCS3, Phosphorylation, 0303 health sciences, Chemistry, General Neuroscience, MESH: STAT3 Transcription Factor, MESH: tau Proteins, 3. Good health, medicine.anatomical_structure, Alzheimer disease, Alzheimer's disease, Signal Transduction, Astrocyte, STAT3 Transcription Factor, Genetically modified mouse, Elevated plus maze, Amyloid, MESH: Mice, Transgenic, Amyloidogenic Proteins, Mice, Transgenic, tau Proteins, Viral vector, 03 medical and health sciences, medicine, Animals, 030304 developmental biology, MESH: Amyloidogenic Proteins, MESH: Phosphorylation, Activator (genetics), Janus Kinase 2, medicine.disease, MESH: Astrocytes, Disease Models, Animal, 030104 developmental biology, Astrocytes, Reactive astrocytes, Neurology (clinical), Tau, MESH: Disease Models, Animal, Geriatrics and Gerontology, Neuroscience, MESH: Alzheimer Disease, 030217 neurology & neurosurgery, Developmental Biology
Abstract: In Alzheimer disease (AD), astrocytes undergo complex changes and become reactive. The consequences of this reaction are still unclear. To evaluate the net impact of reactive astrocytes in AD, we recently developed viral vectors targeting astrocytes that either activate or inhibit the JAK2-STAT3 pathway, a central cascade controlling astrocyte reaction.We aimed to evaluate whether reactive astrocytes contribute to Tau as well as amyloid pathologies in the hippocampus of 3xTg-AD mice, an AD model that develops Tau hyperphosphorylation and aggregation in addition to amyloid deposition. JAK2-STAT3 pathway-mediated modulation of reactive astrocytes in the hippocampus of 3xTg-AD mice, did not significantly influence Tau phosphorylation or amyloid processing and deposition, at early, advanced and terminal stage of the disease. Interestingly, inhibition of the JAK2-STAT3 pathway in hippocampal astrocytes did not improve short-term spatial memory in the Y maze but it reduced anxiety in the elevated plus maze. Our unique approach to specifically manipulate reactive astrocytes in situ show these cells may impact behavioral outcomes without influencing Tau or amyloid pathology.
Published: 2020

32. Les protéinopathies infectieuses de Parkinson et d’Alzheimer

Author: R. Melki, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ANR-17-JPCD-0002,TransPathND,Intraneuronal transport-related pathways across neurodegenerative diseases(2017), ANR-17-JPCD-0005,Protest-70,Protecting protein homeostasis in synucleinopathies and tauopathies by modulating the Hsp70/co-chaperone network(2017), European Project: (grant No 116060),IMPRiND, and European Project: 821522,PD-MitoQUANT - H2020-EU.3.1.7. - Innovative Medicines Initiative 2 (IMI2)
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], General Medicine, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030217 neurology & neurosurgery, 3. Good health
Abstract: International audience; L’apparition de dépôts intra- ou extracellulaires de protéines dans le système nerveux central est le signe distinctif de plusieurs troubles neurodégénératifs progressifs chez l’homme. Les constituants protéiques de ces dépôts et les régions du cerveau touchées diffèrent d’un trouble neurodégénératif à un autre. Jusqu’à récemment, on pensait que le cercle vicieux constitué par l’agrégation de protéines, leur propagation/multiplication et l’accumulation dans le système nerveux central ce ces agrégats était l’apanage de la protéine prion PrP. De récentes données suggèrent que des agrégats de protéines constitués de protéines distinctes de la PrP se propagent et s’amplifient dans le système nerveux central, entraînant différentes maladies. La façon dont les agrégats de la protéine alpha-synucléine circulent entre les cellules, s’amplifient en recrutant de l’alpha-synucléine monomérique endogène et provoquent des synucléinopathies distinctes, n’est pas claire. Je passe en revue ici les preuves expérimentales à l’appui de la propagation des agrégats de l’alpha-synucléine à la manière des agrégats de la protéine prion PrP. Je décris également comment l’alpha-synucléine s’agrège. J’explique aussi comment l’agrégation de l’alpha-synucléine peut conduire à des synucléinopathies distinctes. Je conclus cette revue par une comparaison des propriétés de l’alpha-synucleine et de la protéine Tau dont l’agrégation est impliquée dans différentes tauopathies, dont la maladie d’Alzheimer.
Published: 2020

33. Emerging technologies to study glial cells

Author: Julien Muffat, Carole Escartin, Tirzah Kreisel, Emilie Hangen, Nicole Déglon, Nathalie Linck, Sara Regio, Sybille Rion, Inbal Goshen, Lynette C. Foo, Jaime Grutzendler, Hélène Hirbec, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE12-0027,EpiHD,Rôle des mécanismes épigénétiques dans la maladie de Huntington(2017), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: 0301 basic medicine, Cell type, [SDV]Life Sciences [q-bio], Oligodendrocyte progenitor, Biology, Viral vector, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, In patient, Induced pluripotent stem cell, Neurons, Microglia, Molecular analysis, Oligodendroglia, 030104 developmental biology, medicine.anatomical_structure, nervous system, Neurology, Cell culture, Astrocytes, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroglia, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Development, physiological functions, and pathologies of the brain depend on tight interactions between neurons and different types of glial cells, such as astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells. Assessing the relative contribution of different glial cell types is required for the full understanding of brain function and dysfunction. Over the recent years, several technological breakthroughs were achieved, allowing "glio-scientists" to address new challenging biological questions. These technical developments make it possible to study the roles of specific cell types with medium or high-content workflows and perform fine analysis of their mutual interactions in a preserved environment. This review illustrates the potency of several cutting-edge experimental approaches (advanced cell cultures, induced pluripotent stem cell (iPSC)-derived human glial cells, viral vectors, in situ glia imaging, opto- and chemogenetic approaches, and high-content molecular analysis) to unravel the role of glial cells in specific brain functions or diseases. It also illustrates the translation of some techniques to the clinics, to monitor glial cells in patients, through specific brain imaging methods. The advantages, pitfalls, and future developments are discussed for each technique, and selected examples are provided to illustrate how specific "gliobiological" questions can now be tackled.
Published: 2020

34. Cortical astrocytes develop in a plastic manner at both clonal and cellular levels

Author: Jason Durand, Sio-Hoi Ieng, Edwin Hernández-Garzón, Emmanuel Beaurepaire, Solène Clavreul, Gilles Bonvento, Lamiae Abdeladim, Raphaëlle Barry, Dragos Niculescu, Jean Livet, Karine Loulier, Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Optique et Biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM)
Subjects: 0301 basic medicine, Science, Cellular differentiation, Cell Plasticity, General Physics and Astronomy, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Glial development, medicine, Animals, Cell Lineage, Progenitor cell, lcsh:Science, Spatial organization, Cell Proliferation, Cerebral Cortex, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], Multidisciplinary, Neocortex, Cell growth, Cell Differentiation, General Chemistry, Clone Cells, 030104 developmental biology, medicine.anatomical_structure, Astrocytes, Gliogenesis, Local environment, lcsh:Q, Neuroscience, 030217 neurology & neurosurgery, Astrocyte
Abstract: Astrocytes play essential roles in the neural tissue where they form a continuous network, while displaying important local heterogeneity. Here, we performed multiclonal lineage tracing using combinatorial genetic markers together with a new large volume color imaging approach to study astrocyte development in the mouse cortex. We show that cortical astrocyte clones intermix with their neighbors and display extensive variability in terms of spatial organization, number and subtypes of cells generated. Clones develop through 3D spatial dispersion, while at the individual level astrocytes acquire progressively their complex morphology. Furthermore, we find that the astroglial network is supplied both before and after birth by ventricular progenitors that scatter in the neocortex and can give rise to protoplasmic as well as pial astrocyte subtypes. Altogether, these data suggest a model in which astrocyte precursors colonize the neocortex perinatally in a non-ordered manner, with local environment likely determining astrocyte clonal expansion and final morphotype., Previous studies on astrocyte development have led to controversial results due to a lack of pertinent tools. Here, authors analyze large numbers of astrocyte clones generated by nearby cortical progenitors using the MAGIC Markers strategy and ChroMS 3D imaging, and show that clonally-related astrocytes organize in a non-stereotyped manner and that cortical astrocyte subtypes are not intrinsically specified.
Published: 2019

35. Transmission of amyloid-beta and tau pathologies is associated with cognitive impairments in a primate

Author: Charles Duyckaerts, Martine Guillermier, Stéphane Haïk, Fanny Petit, Marc Dhenain, Suzanne Lam, Jean-Luc Picq, Anne-Sophie Hérard, Luc Buée, Susana Boluda, Sabiha Eddarkaoui, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Excellence Laboratory LabEx DISTALZ, Université de Lille, CHU Lille, Fonctionnement et Dysfonctionnement Cognitifs : Les âges de la vie (DysCo), Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN), Brain Bank Neuro-C. E. B. Neuropathology Network: Franck Letournel, Marie-Laure Martin-Négrier, Maxime Faisant, Catherine Godfraind, Jean Boutonnat, Claude-Alain Maurage, Vincent Deramecourt, Mathilde Duchesne, David Meyronet, Tanguy Fenouil, André Mauès de Paula, Valérie Rigau, Fanny Vandenbos-Burel, Danielle Seilhean, Charles Duyckaerts, Susana Boluda, Isabelle Plu, Dan Christian Chiforeanu, Annie Laquerrière, Florent Marguet, Béatrice Lannes, Benoît Lhermitte, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), BUEE, Luc, Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pathology, medicine.medical_specialty, Tau pathology, Amyloid beta, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Iatrogenic Disease, tau Proteins, Cerebral atrophy, Corpus callosum, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, Cortex (anatomy), medicine, Animals, Humans, Transmission, Cognitive Dysfunction, Cognitive decline, RC346-429, 030304 developmental biology, 0303 health sciences, Amyloid beta-Peptides, biology, business.industry, Research, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, Human brain, Alzheimer's disease, medicine.disease, Entorhinal cortex, 3. Good health, medicine.anatomical_structure, Posterior cingulate, biology.protein, Prion, Neurology. Diseases of the nervous system, Neurology (clinical), Amyloid-β pathology, Cheirogaleidae, business, 030217 neurology & neurosurgery
Abstract: Amyloid-β (Aβ) pathology transmission has been described in patients following iatrogenic exposure to compounds contaminated with Aβ proteins. It can induce cerebral Aβ angiopathy resulting in brain hemorrhages and devastating clinical impacts. Iatrogenic transmission of tau pathology is also suspected but not experimentally proven. In both scenarios, lesions were detected several decades after the putatively triggering medico-surgical act. There is however little information regarding the cognitive repercussions in individuals who do not develop cerebral hemorrhages. In the current study, we inoculated the posterior cingulate cortex and underlying corpus callosum of young adult primates (Microcebus murinus) with either Alzheimer’s disease or control brain extracts. This led to widespread Aβ and tau pathologies in all of the Alzheimer-inoculated animals following a 21-month-long incubation period (n = 12) whereas none of the control brain extract-inoculated animals developed such lesions (n = 6). Aβ deposition affected almost all cortical regions. Tau pathology was also detected in Aβ-deposit-free regions distant from the inoculation sites (e.g. in the entorhinal cortex), while some regions adjacent, but not connected, to the inoculation sites were spared (e.g. the occipital cortex). Alzheimer-inoculated animals developed cognitive deficits and cerebral atrophy compared to controls. These pathologies were induced using two different batches of Alzheimer brain extracts. This is the first experimental demonstration that tau can be transmitted by human brain extracts inoculations in a primate. We also showed for the first time that the transmission of widespread Aβ and tau pathologies can be associated with cognitive decline. Our results thus reinforce the need to organize a systematic monitoring of individuals who underwent procedures associated with a risk of Aβ and tau iatrogenic transmission. They also provide support for Alzheimer brain-inoculated primates as relevant models of Alzheimer pathology.
Published: 2021

36. Multiparametric MRI for the Research of Early Biomarkers in Polyglutamine Diseases

Author: Pérot, Jean-Baptiste, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, Emmanuel Brouillet, Julien Flament, Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Gene therapy, Modèles animaux, [SCCO.NEUR]Cognitive science/Neuroscience, Neurodegenerative diseases, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Maladies neurodégénératives, Thérapie génique, IRM, Animal models
Abstract: PolyQ diseases are inherited neurodegenerative diseases caused by the expansion of CAG repeats on a specific gene. While no efficient treatment has been discovered yet, recent advances in gene therapy let hope for a gene silencing treatment directly targeting the cause of the disease. However, evaluation of the efficacy of these therapies is compromised by the difficulty to evaluate the progression of the disease on early stages, while brain impairments are still reversible. Thus, the research of biomarkers of the presymptomatic phase of PolyQ diseases is a major issue for successful development of therapies. MRI is a versatile technique that proposes a diversity of applications with the ability to measure morphometric, metabolic, microstructural, or functional parameters in patients or in the brain of rodent models. In this thesis, we present the results of three longitudinal, multiparametric MRI studies on rodent models of Huntington’s Disease (HD) and Spinocerebellar Ataxia type 7 (SCA7). The first study, on CAG140 mouse model of HD, showed a vulnerability of white matter in this model, allowing a better understanding of pathogenesis. The second study shows the results of evaluation of an antisense oligonucleotide in a rat model of HD. This trial showed the efficacy of the treatment but also highlighted the necessity to perfectly control experimental conditions for robust metabolic imaging. The third study presents the evaluation of gene therapy by interfering RNA in a mouse model of SCA7. Results show a beneficial effect of injection of viral vectors, however the specific effect of gene silencing needs requires further investigation. Overall, this thesis work demonstrates the pertinence of longitudinal, multiparametric MRI for the research of early biomarkers of PolyQ diseases and provides recommendations for conducting this kind of study.; Les maladies par expansion de polyglutamine sont des maladies neurodégénératives héréditaires causées par l’expansion de répétitions CAG. Les récentes avancées en thérapie génique permettent d’espérer un traitement par extinction du gène muté responsable de la maladie. Cependant, la recherche est ralentie par la difficulté à évaluer l’efficacité de ces thérapies lorsqu’elles sont administrées à un stade précoce, quand les atteintes cérébrales dues aux mécanismes de pathogénèses sont encore potentiellement réversibles. La recherche de biomarqueurs non-invasifs de la phase présymptomatique des maladies par expansion de polyglutamine est ainsi un enjeu majeur pour le développement de thérapies. L’IRM offre une diversité d’applications qui permet de mesurer des paramètres morphométriques, métaboliques,microstructuraux ou encore fonctionnels dans le cerveau de patients ou de modèles animaux de ces maladies. Ce travail de thèse présente les résultats de trois études longitudinales d’IRM multiparamétrique réalisées sur des modèles rongeurs de la maladie de Huntington (MH) et de l’ataxie spinocérébelleuse de type 7 (ASC7). La première étude sur le modèle CAG140 de la MH a montré une vulnérabilité de la matière blanche dans ce modèle, permettant une meilleure compréhension de la progression de la pathologie. La seconde étude montre les résultats d’un essai thérapeutique d’oligonucléotides antisens dans un modèle rat de la MH. Cet essai a permis de montrer l’efficacité de la thérapie mais a également pointé du doigt l’importance du contrôle des conditions expérimentales pour l’imagerie du métabolisme cérébral. La troisième étude présente un essai thérapeutique par ARN interférant dans un modèle souris d’ASC7. Les résultats montrent une réponse dessouris à l’injection de vecteurs viraux, bien que l’effet bénéfique apporté spécifiquement par la thérapie nécessite plus d’investigations. Au global, ce travail de thèse démontre la pertinence de l’IRM longitudinale et multiparamétrique pour la recherche de biomarqueurs précoces des maladies par expansion de polyglutamine et propose des recommandations pour la conduite de ce type d’étude.
Published: 2021

37. Disrupting D1-NMDA or D2-NMDA receptor heteromerization prevents cocaine's rewarding effects but preserves natural reward processing

Author: Marie-Charlotte Allichon, Ying Zhu, Roman Walle, Vincent Kappes, Andry Andrianarivelo, Naguib Mechawar, Jocelyne Caboche, Jacques Barik, Nicolas Heck, Paula A. Pousinha, Peter Vanhoutte, Véronique De Smedt-Peyrusse, Pierre Trifilieff, Gustavo Turecki, Anna Petitbon, Estefani Saint-Jour, Sebastian P. Fernandez, Vanesa Ortiz, Jonathan A. Javitch, Charlène Joséphine, Alexis-Pierre Bemelmans, Sandrine Betuing, Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Bioinformatique [IBPS] (IBPS-Artbio), Institut de Biologie Paris Seine (IBPS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Nutrition et Neurobiologie intégrée (NutriNeuro), Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), New York State Psychiatric Institute, Columbia University [New York], Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], ANR-16-CE16-0022,SynLip,Impact de la composition lipidique membranaire sur la transmission dopaminergique dépendante du récepteur D2 et la motivation(2016), ANR-18-CE37-0003,DropStress,Cibler les complexes formés par les récepteurs de la dopamine et du glutamate pour atténuer les pathologies liées au stress(2018), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Polytechnique de Bordeaux (Bordeaux INP), CEA- Saclay (CEA), Centre National de la Recherche Scientifique (CNRS), and FERNANDEZ, SEBASTIAN PABLO
Subjects: media_common.quotation_subject, [SDV]Life Sciences [q-bio], Nucleus accumbens, Biology, 03 medical and health sciences, 0302 clinical medicine, Dopamine, Dopamine receptor D2, mental disorders, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, media_common, 0303 health sciences, Multidisciplinary, Addiction, Glutamate receptor, SciAdv r-articles, 3. Good health, [SDV] Life Sciences [q-bio], nervous system, Dopamine receptor, Excitatory postsynaptic potential, NMDA receptor, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, 030217 neurology & neurosurgery, Research Article, Signal Transduction, medicine.drug
Abstract: Description, D2R-NMDAR receptor heteromers are potential therapeutic targets in drug addiction., Addictive drugs increase dopamine in the nucleus accumbens (NAc), where it persistently shapes excitatory glutamate transmission and hijacks natural reward processing. Here, we provide evidence, from mice to humans, that an underlying mechanism relies on drug-evoked heteromerization of glutamate N-methyl-d-aspartate receptors (NMDAR) with dopamine receptor 1 (D1R) or 2 (D2R). Using temporally controlled inhibition of D1R-NMDAR heteromerization, we unraveled their selective implication in early phases of cocaine-mediated synaptic, morphological, and behavioral responses. In contrast, preventing D2R-NMDAR heteromerization blocked the persistence of these adaptations. Interfering with these heteromers spared natural reward processing. Notably, we established that D2R-NMDAR complexes exist in human samples and showed that, despite a decreased D2R protein expression in the NAc, individuals with psychostimulant use disorder display a higher proportion of D2R forming heteromers with NMDAR. These findings contribute to a better understanding of molecular mechanisms underlying addiction and uncover D2R-NMDAR heteromers as targets with potential therapeutic value.
Published: 2021

38. On the generalizability of diffusion MRI signal representations across acquisition parameters, sequences and tissue types: chronicles of the MEMENTO challenge

Author: Daniel C. Alexander, Andrada Ianus, Zhijie Zhang, Mingwu Jin, Geert Jan Biessels, Mauro Zucchelli, Santiago Aja-Fernández, Ariel Rokem, Vesna Prchkovska, Rachid Deriche, Alexander Leemans, Matteo Frigo, Vishwesh Nath, Eleftherios Garyfallidis, Rutger Fick, Derek K. Jones, Evren Özarslan, Maryam Afzali, Marco Palombo, Martijn Froeling, Haoze Chen, Jan Sijbers, Abib Alimi, Prasanna Parvathaneni, Paulo Rodrigues, Sara Sedlar, Tomasz Pieciak, Stefan Endres, Markus Nilsson, Fabian Bogusz, Bennett A. Landman, Shreyas Fadnavis, Enes Albay, Noam Shemesh, Jan Morez, Irina Sánchez, Ben Jeurissen, Fengxiang Wang, Alberto De Luca, Samuel Deslauriers-Gauthier, Kurt G. Schilling, Hui Zhang, Image sciences institute - University of Utrecht (ISI), University Medical Center [Utrecht], Utrecht Brain Center [UMC], Champalimaud Centre for the Unknown [Lisbon], Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Department of Forest Ecology and Management, Swedish University of Agricultural Sciences (SLU), Computational Imaging of the Central Nervous System (ATHENA), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Istanbul Technical University (ITÜ), TRIBVN Healthcare, Cardiff University's Brain Research Imaging Centre [Cardiff] (CUBRIC), School of Psychology [Cardiff University], Cardiff University-Cardiff University, Department of Automatics (AGH-UST), AGH University of Science and Technology [Krakow, PL] (AGH UST), Laboratorio de Procesado de Imagen [Valladolid] (LPI), Université de Valladolid, Department of Biomedical Engineering [Linköping], Linköping University (LIU), Taiyuan University of Technology, University of Texas at Arlington [Arlington], NVIDIA (NVIDIA), National Institutes of Health [Bethesda] (NIH), Vision Lab [Antwerp], University of Antwerp (UA), Indiana University [Bloomington], Indiana University System, Institute of Materials Engineering [Bremen] (IWT ), University of Bremen, University of Washington [Seattle], QMENTA Inc, Vanderbilt University [Nashville], Vanderbilt University Medical Center [Nashville], ANR-19-P3IA-0002,3IA@cote d'azur,3IA Côte d'Azur(2019), European Project: 694665,H2020 ERC,ERC-2015-AdG,CoBCoM(2016), UMC Utrecht, Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Physics, The University of Texas at Arlington, United States, and Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville
Subjects: Mean squared error, Databases, Factual, Computer science, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Cognitive Neuroscience, Neurosciences. Biological psychiatry. Neuropsychiatry, computer.software_genre, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Mice, 0302 clinical medicine, Bayesian information criterion, Voxel, Encoding (memory), Image Processing, Computer-Assisted, Animals, Humans, Generalizability theory, Computer. Automation, Hyperparameter, Bioinformatics (Computational Biology), business.industry, Physics, Brain, Pattern recognition, Data point, Diffusion Magnetic Resonance Imaging, Neurology, Bioinformatik (beräkningsbiologi), Human medicine, Artificial intelligence, Neural Networks, Computer, business, computer, 030217 neurology & neurosurgery, RC321-571, Diffusion MRI
Abstract: Diffusion MRI (dMRI) has become an invaluable tool to assess the microstructural organization of brain tissue. Depending on the specific acquisition settings, the dMRI signal encodes specific properties of the underlying diffusion process. In the last two decades, several signal representations have been proposed to fit the dMRI signal and decode such properties. Most methods, however, are tested and developed on a limited amount of data, and their applicability to other acquisition schemes remains unknown. With this work, we aimed to shed light on the generalizability of existing dMRI signal representations to different diffusion encoding parameters and brain tissue types. To this end, we organized a community challenge - named MEMENTO, making available the same datasets for fair comparisons across algorithms and techniques. We considered two state-of-the-art diffusion datasets, including single-diffusion-encoding (SDE) spin-echo data from a human brain with over 3820 unique diffusion weightings (the MASSIVE dataset), and double (oscillating) diffusion encoding data (DDE/DODE) of a mouse brain including over 2520 unique data points. A subset of the data sampled in 5 different voxels was openly distributed, and the challenge participants were asked to predict the remaining part of the data. After one year, eight participant teams submitted a total of 80 signal fits. For each submission, we evaluated the mean squared error, the variance of the prediction error and the Bayesian information criteria. The received submissions predicted either multi-shell SDE data (37%) or DODE data (22%), followed by cartesian SDE data (19%) and DDE (18%). Most submissions predicted the signals measured with SDE remarkably well, with the exception of low and very strong diffusion weightings. The prediction of DDE and DODE data seemed more challenging, likely because none of the submissions explicitly accounted for diffusion time and frequency. Next to the choice of the model, decisions on fit procedure and hyperparameters play a major role in the prediction performance, highlighting the importance of optimizing and reporting such choices. This work is a community effort to highlight strength and limitations of the field at representing dMRI acquired with trending encoding schemes, gaining insights into how different models generalize to different tissue types and fiber configurations over a large range of diffusion encodings. Funding Agencies|European Research Council (ERC) under the European UnionEuropean Research Council (ERC) [694665]; French government, through the 3IA Cote DAzur Investments in the Future project [ANR-19-P3IA-0002]; EPSRCUK Research & Innovation (UKRI)Engineering & Physical Sciences Research Council (EPSRC) [EP/N018702/1, MR/T020296/1, ISLRA-2009]; European Space AgencyEuropean Space AgencyEuropean Commission; Belgian Science Policy Office-ProdexBelgian Federal Science Policy Office; Research Foundation Flanders (FWO Vlaanderen)FWO [12M3119N, G0D7216N]; Wellcome Trust Investigator AwardWellcome Trust [096646/Z/11/Z]; Wellcome Trust Strategic AwardWellcome Trust [104943/Z/14/Z]; Polish National Agency for Academic ExchangePolish National Agency for Academic Exchange (NAWA) [PN/BEK/2019/1/00421]; Ministry of Science and Higher Education (Poland)Ministry of Science and Higher Education, Poland [692/STYP/13/2018]; AGH Science and Technology, Poland [16.16.120.773]; Linkoping University (LiU) Center for Industrial Information Technology (CENIIT); LiU Cancer [VINNOVA/ITEA3 17021 IMPACT]; Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [RMX18-0056]; "la Caixa" FoundationLa Caixa Foundation [100010434]; European UnionEuropean Commission [847648, LCF/BQ/PI20/11760029]; Ministerio de Ciencia e Innovacion" of SpainSpanish Government [RTI2018-094569-B-I00]; National Institute for Biomedical Imaging [5R01EB027585-02]
Published: 2021

39. Structural mapping techniques distinguish the surfaces of fibrillar 1N3R and 1N4R human tau

Author: Virginie Redeker, Karine Madiona, Ronald Melki, Emilie Caroux, Centre National de la Recherche Scientifique (CNRS), Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ANR-17-JPCD-0005,Protest-70,Protecting protein homeostasis in synucleinopathies and tauopathies by modulating the Hsp70/co-chaperone network(2017), ANR-17-JPCD-0002,TransPathND,Intraneuronal transport-related pathways across neurodegenerative diseases(2017), and Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB)
Subjects: PiD, Pick's disease, Cryo-electron microscopy, Pronase, Biochemistry, PVDF, polyvinylidene difluoride, 0302 clinical medicine, Protein structure, MS2, fragmentation mass spectrum, N-TOP, N-terminal-oriented proteomics, cryo-EM, cryo-electron microscopy, SDS-PAGE, sodium dodecyl sulfate–polyacrylamide gel electrophoresis, mass spectrometry, MALDI-TOF-TOF, matrix assisted laser desorption/ionization-time-of-flight-time-of-flight, chemistry.chemical_classification, 0303 health sciences, CID, collision-Induced dissociation, medicine.diagnostic_test, Chemistry, TMPP(, N-succinimidyloxycarbonylmethyl)-tris(2,4,6-trimethoxyphenyl)-phosphonium, DTT, 1,4-dithiotheritol, NHS-biotin, N-hydroxysulfosuccinimide biotin, Amino acid, PSP, progressive supranuclear palsy, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], AD, Alzheimer's disease, Research Article, CBD, corticobasal degeneration, AGD, argyrophilic grain disease, FDR, false discovery rate, Proteolysis, tau fibrils, tau Proteins, macromolecular substances, Fibril, Peptide Mapping, TFA, trifluoroacetic acid, 03 medical and health sciences, Protein Aggregates, Protein Domains, PBS, phosphate buffered saline, protein conformation, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, TEM, transmission electron microscopy, Molecular Biology, TD, tangle disease, 030304 developmental biology, htau, human tau, nanoLC-MS/MS, nanoflow liquid chromatography combined to tandem mass spectrometry bromide, tauopathies, Alternative splicing, Cell Biology, medicine.disease, structural proteomics, MS, mass spectrometry, chemical surface modification, Biophysics, AEBSF, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride, Pick's disease, 030217 neurology & neurosurgery, limited proteolysis
Abstract: International audience; The rigid core of intracellular tau filaments from Alzheimer’s disease (AD), Pick’s disease (PiD), and Corticobasal disease (CBD) brains has been shown to differ in their cryo-EM atomic structure. Despite providing critical information on the intimate arrangement of a fraction of htau molecule within the fibrillar scaffold, the cryo-EM studies neither yield a complete picture of tau fibrillar assemblies structure nor contribute insights into the surfaces that define their interactions with numerous cellular components. Here, using proteomic approaches such as proteolysis and molecular covalent painting, we mapped the exposed amino acid stretches at the surface and those constituting the fibrillar core of in vitro-assembled fibrils of human htau containing one N-terminal domain and three (1N3R) or four (1N4R) C-terminal microtubule-binding repeat domains as a result of alternative splicing. Using limited proteolysis, we identified the proteolytic fragments composing the molecular “bar-code” for each type of fibril. Our results are in agreement with structural data reported for filamentous tau from AD, PiD, and CBD cases predigested with the protease pronase. Finally, we report two amino acid stretches, exposed to the solvent in 1N4R not in 1N3R htau, which distinguish the surfaces of these two kinds of fibrils. Our findings open new perspectives for the design of highly specific ligands with diagnostic and therapeutic potential.
Published: 2021

40. Multi-transcriptomic analysis points to early organelle dysfunction in human astrocytes in Alzheimer's disease

Author: Elena Galea, Laura D. Weinstock, Raquel Larramona-Arcas, Alyssa F. Pybus, Lydia Giménez-Llort, Carole Escartin, Levi B. Wood, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, Georgia Institute of Technology [Atlanta], Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Universitat Autònoma de Barcelona (UAB), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Organelles, 0303 health sciences, Gene Expression Profiling, Neurosciences. Biological psychiatry. Neuropsychiatry, Alzheimer's disease, Hierarchical clustering, MCI, Article, Mitochondria, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Neurology, Alzheimer Disease, Perisynaptic astrocyte processes, Astrocytes, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive Dysfunction, Transcriptome, 030217 neurology & neurosurgery, RC321-571, 030304 developmental biology
Abstract: International audience; The phenotypic transformation of astrocytes in Alzheimer’s disease (AD) is still not well understood. Recentanalyses based on single-nucleus RNA sequencing of postmortem Alzheimer’s disease (AD) samples are limited bythe low number of sequenced astrocytes, small cohort sizes, and low number of differentially expressed genesdetected. To optimize the detection of astrocytic genes, we employed a novel strategy consisting of the localization of pre-determined astrocyte and neuronal gene clusters in publicly available whole-brain transcriptomes.Specifically, we used cortical transcriptomes from 766 individuals, including cognitively normal subjects(Controls), and people diagnosed with mild cognitive impairment (MCI) or dementia due to AD. Samples camefrom three independent cohorts organized by the Mount Sinai Hospital, the Mayo Clinic, and the Religious OrderStudy/Memory and Aging Project (ROSMAP). Astrocyte- and neuron-specific gene clusters were generated fromhuman brain cell-type specific RNAseq data using hierarchical clustering and cell-type enrichment scoring. Genesfrom each cluster were manually annotated according to cell-type specific functional Categories. Gene SetVariation Analysis (GSVA) and Principal Component Analysis (PCA) were used to establish changes in thesefunctional categories among clinical cohorts. We highlight three novel findings of the study. First, individualswith the same clinical diagnosis were molecularly heterogeneous. Particularly in the Mayo Clinic and ROSMAPcohorts, over 50% of Controls presented down-regulation of genes encoding synaptic proteins typical of AD,whereas 30% of patients diagnosed with dementia due to AD presented Control-like transcriptomic profiles.Second, down-regulation of neuronal genes related to synaptic proteins coincided, in astrocytes, with upregulation of genes related to perisynaptic astrocytic processes (PAP) and down-regulation of genes encoding endolysosomal and mitochondrial proteins. Third, down-regulation of astrocytic mitochondrial genes inverselycorrelated with the disease stages defined by Braak and CERAD scoring. Finally, we interpreted these changes asmaladaptive or adaptive from the point of view of astrocyte biology in a model of the phenotypical transformation of astrocytes in AD. The main prediction is that early malfunction of the astrocytic endolysosomal system, associated with progressive mitochondrial dysfunction, contribute to Alzheimer’s disease. If this prediction is correct, therapies preventing organelle dysfunction in astrocytes may be beneficial in preclinical and clinical AD.
Published: 2021

41. Whole brain mapping of glutamate distribution in adult and old primates at 11.7T

Author: Clément M. Garin, Nachiket A. Nadkarni, Jérémy Pépin, Julien Flament, Marc Dhenain, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Primates, Aging, Brain Mapping, GluCEST, Cognitive Neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, Glutamic Acid, Neurosciences. Biological psychiatry. Neuropsychiatry, Magnetic Resonance Imaging, Neurology, Animals, Humans, Mouse lemur, Cerebral network, Glutamate, RC321-571
Abstract: Glutamate is the amino acid with the highest cerebral concentration. It plays a central role in brain metabolism. It is also the principal excitatory neurotransmitter in the brain and is involved in multiple cognitive functions. Alterations of the glutamatergic system may contribute to the pathophysiology of many neurological disorders. For example, changes of glutamate availability are reported in rodents and humans during Alzheimer's and Huntington's diseases, epilepsy as well as during aging. Most studies evaluating cerebral glutamate have used invasive or spectroscopy approaches focusing on specific brain areas. Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) is a recently developed imaging technique that can be used to study relative changes in glutamate distribution in the entire brain with higher sensitivity and at higher resolution than previous techniques. It thus has strong potential clinical applications to assess glutamate changes in the brain. High field is a key condition to perform gluCEST images with a meaningful signal to noise ratio. Thus, even if some studies started to evaluate gluCEST in humans, most studies focused on rodent models that can be imaged at high magnetic field. In particular, systematic characterization of gluCEST contrast distribution throughout the whole brain has never been performed in humans or non-human primates. Here, we characterized for the first time the distribution of the gluCEST contrast in the whole brain and in large-scale networks of mouse lemur primates at 11.7 Tesla. Because of its small size, this primate can be imaged in high magnetic field systems. It is widely studied as a model of cerebral aging or Alzheimer's disease. We observed high gluCEST contrast in cerebral regions such as the nucleus accumbens, septum, basal forebrain, cortical areas 24 and 25. Age-related alterations of this biomarker were detected in the nucleus accumbens, septum, basal forebrain, globus pallidus, hypophysis, cortical areas 24, 21, 6 and in olfactory bulbs. An age-related gluCEST contrast decrease was also detected in specific neuronal networks, such as fronto-temporal and evaluative limbic networks. These results outline regional differences of gluCEST contrast and strengthen its potential to provide new biomarkers of cerebral function in primates.
Published: 2021

42. Microglial inclusions and neurofilament light chain release follow neuronal $\alpha$-synuclein lesions in long-term brain slice cultures

Author: Barth, Melanie, Bacioglu, Mehtap, Schwarz, Niklas, Novotny, Renata, Brandes, Janine, Welzer, Marc, Mazzitelli, Sonia, Häsler, Lisa, Schweighauser, Manuel, Wuttke, Thomas, Kronenberg-Versteeg, Deborah, Fog, Karina, Ambjørn, Malene, Alik, Ania, Melki, Ronald, Kahle, Philipp, Shimshek, Derya, Koch, Henner, Jucker, Mathias, Tanriöver, Gaye, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de la Recherche Scientifique (CNRS), Novartis Institutes for BioMedical Research (NIBR), Helmholtz-Institute for Biomedical Engineering [RWTH Aachen University], European Project: (grant No 116060),IMPRiND, and Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB)
Subjects: Alpha-synuclein, [SDV]Life Sciences [q-bio], Microglia, Slice culture, Neurofilament light chain
Abstract: International audience; Background: Proteopathic brain lesions are a hallmark of many age-related neurodegenerative diseases including synucleinopathies and develop at least a decade before the onset of clinical symptoms. Thus, understanding of the initiation and propagation of such lesions is key for developing therapeutics to delay or halt disease progression. Methods: Alpha-synuclein (αS) inclusions were induced in long-term murine and human slice cultures by seeded aggregation. An αS seed-recognizing human antibody was tested for blocking seeding and/or spreading of the αS lesions. Release of neurofilament light chain (NfL) into the culture medium was assessed. Results: To study initial stages of α-synucleinopathies, we induced αS inclusions in murine hippocampal slice cultures by seeded aggregation. Induction of αS inclusions in neurons was apparent as early as 1week post-seeding, followed by the occurrence of microglial inclusions in vicinity of the neuronal lesions at 2-3 weeks. The amount of αS inclusions was dependent on the type of αS seed and on the culture's genetic background (wildtype vs A53T-αS genotype). Formation of αS inclusions could be monitored by neurofilament light chain protein release into the culture medium, a fluid biomarker of neurodegeneration commonly used in clinical settings. Local microinjection of αS seeds resulted in spreading of αS inclusions to neuronally connected hippocampal subregions, and seeding and spreading could be inhibited by an αS seed-recognizing human antibody. We then applied parameters of the murine cultures to surgical resection-derived adult human long-term neocortical slice cultures from 22 to 61-yearold donors. Similarly, in these human slice cultures, proof-of-principle induction of αS lesions was achieved at 1week post-seeding in combination with viral A53T-αS expressions. Conclusion: The successful translation of these brain cultures from mouse to human with the first reported induction of human αS lesions in a true adult human brain environment underlines the potential of this model to study proteopathic lesions in intact mouse and now even aged human brain environments.
Published: 2021

43. LAG3 is not expressed in human and murine neurons and does not modulate α‐synucleinopathies

Author: Emmenegger, Marc, De Cecco, Elena, Hruska-Plochan, Marian, Eninger, Timo, Schneider, Matthias M, Barth, Melanie, Tantardini, Elena, De Rossi, Pierre, Bacioglu, Mehtap, Langston, Rebekah G, Kaganovich, Alice, Bengoa-Vergniory, Nora, Gonzalez-Guerra, Andrès, Avar, Merve, Heinzer, Daniel, Reimann, Regina, Häsler, Lisa M, Herling, Therese W, Matharu, Naunehal S, Landeck, Natalie, Luk, Kelvin, Melki, Ronald, Kahle, Philipp J, Hornemann, Simone, Knowles, Tuomas PJ, Cookson, Mark R, Polymenidou, Magdalini, Jucker, Mathias, Aguzzi, Adriano, Universität Zürich [Zürich] = University of Zurich (UZH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Cambridge [UK] (CAM), National Institutes of Health [Bethesda] (NIH), University of Oxford [Oxford], Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Tübingen, National Centre for Competence in Research (NCCR) RNA & Disease (51NF40-182880), European Project: 670958,H2020,ERC-2014-ADG,PRION2020(2015), European Project: 674979,H2020,H2020-MSCA-ITN-2015,NANOTRANS(2016), European Project: (grant No 116060),IMPRiND, University of Oxford, Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Emmenegger, Marc [0000-0002-6073-8811], De Cecco, Elena [0000-0002-0148-2596], Hruska-Plochan, Marian [0000-0002-9253-4362], Schneider, Matthias M [0000-0002-1894-1859], Tantardini, Elena [0000-0001-9189-3390], Bacioglu, Mehtap [0000-0003-0304-7026], Bengoa-Vergniory, Nora [0000-0002-3700-0464], Avar, Merve [0000-0003-4665-5558], Heinzer, Daniel [0000-0002-3282-4042], Landeck, Natalie [0000-0002-8399-4009], Luk, Kelvin [0000-0002-6591-6269], Melki, Ronald [0000-0003-0000-7096], Hornemann, Simone [0000-0002-2674-9891], Cookson, Mark R [0000-0002-1058-3831], Jucker, Mathias [0000-0001-9045-1072], Aguzzi, Adriano [0000-0002-0344-6708], Apollo - University of Cambridge Repository, Hruska‐Plochan, Marian [0000-0002-9253-4362], Bengoa‐Vergniory, Nora [0000-0002-3700-0464], University of Zurich, and Aguzzi, Adriano
Subjects: Medicine (General), prionoids, Synucleinopathies, 10208 Institute of Neuropathology, 610 Medicine & health, Mice, Transgenic, QH426-470, Article, Mice, R5-920, α-synuclein, Genetics, Animals, Humans, ddc:610, Neurons, α‐synuclein, neurodegeneration, Parkinson Disease, Articles, nervous system diseases, EMBO27, 1313 Molecular Medicine, genetics [alpha-Synuclein], alpha-Synuclein, 570 Life sciences, biology, Molecular Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 11493 Department of Quantitative Biomedicine, Neuroscience, LAG3
Abstract: Funder: University of Zurich and University Hospital of Zurich, Funder: NOMIS Stiftung (NOMIS Foundation); Id: http://dx.doi.org/10.13039/501100008483, Funder: Forschungskredit University of Zurich, While the initial pathology of Parkinson’s disease and other α‐synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α‐synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α‐synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α‐synuclein pathology ex vivo. The overall survival of A53T α‐synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α‐synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α‐synucleinopathies is not universally valid.
Published: 2021
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44. Longitudinal multimodal MRI characterization of a knock-in mouse model of Huntington's disease reveals early gray and white matter alterations

Author: Jean-Baptiste Pérot, Marina Célestine, Marco Palombo, Marc Dhenain, Sandrine Humbert, Emmanuel Brouillet, Julien Flament, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and ANR-17-CE12-0027,EpiHD,Rôle des mécanismes épigénétiques dans la maladie de Huntington(2017)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, Glutamic Acid, General Medicine, White Matter, Magnetic Resonance Imaging, Mice, Disease Models, Animal, Huntington Disease, Diffusion Tensor Imaging, Genetics, Animals, Molecular Biology, Genetics (clinical)
Abstract: Pathogenesis of the inherited neurodegenerative disorder Huntington’s disease (HD) is progressive with a long presymptomatic phase in which subtle changes occur up to 15 years before the onset of symptoms. Thus, there is a need for early, functional biomarker to better understand disease progression and to evaluate treatment efficacy far from onset. Recent studies have shown that white matter may be affected early in mutant HTT gene carriers. A previous study performed on 12 months old Ki140CAG mice showed reduced glutamate level measured by Chemical Exchange Saturation Transfer of glutamate (gluCEST), especially in the corpus callosum. In this study, we scanned longitudinally Ki140CAG mice with structural MRI, diffusion tensor imaging, gluCEST and magnetization transfer imaging, in order to assess white matter integrity over the life of this mouse model characterized by slow progression of symptoms. Our results show early defects of diffusion properties in the anterior part of the corpus callosum at 5 months of age, preceding gluCEST defects in the same region at 8 and 12 months that spread to adjacent regions. At 12 months, frontal and piriform cortices showed reduced gluCEST, as well as the pallidum. MT imaging showed reduced signal in the septum at 12 months. Cortical and striatal atrophy then appear at 18 months. Vulnerability of the striatum and motor cortex, combined with alterations of anterior corpus callosum, seems to point out the potential role of white matter in the brain dysfunction that characterizes HD and the pertinence of gluCEST and DTI as biomarkers in HD.
Published: 2021

45. Astrocytes close the mouse critical period for visual plasticity

Author: Julien Moulard, Pascal Ezan, Glenn Dallérac, Rachel Breton, Alexis-Pierre Bemelmans, Jonathan Zapata, Nathalie Rouach, Chantal Milleret, Kevin Samama, Charles-Félix Calvo, Pierre Billuart, Jérôme Ribot, Florent Dingli, Valentin Sabatet, Matthieu X Moreau, Damarys Loew, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Mass Spectrometry and Proteomics Laboratory, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Cell signaling, Interneuron, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Connexin, Biology, MMP9, Article, GTP Phosphohydrolases, 03 medical and health sciences, Mice, 0302 clinical medicine, Interneurons, Neuroplasticity, medicine, Extracellular, Connexin 30, Animals, Visual Cortex, Mice, Knockout, Multidisciplinary, Neuronal Plasticity, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Critical Period, Psychological, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Enzyme Activation, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Visual cortex, Matrix Metalloproteinase 9, Astrocytes, Synapses, rhoA GTP-Binding Protein, Neuroscience, 030217 neurology & neurosurgery, Astrocyte
Abstract: How astrocytes close a critical period During the visual critical period, brain circuits are rewired to adjust to sensory input. Closure of the critical period stabilizes the circuits. Looking at development in the mouse visual cortex, Ribot et al. found that astrocytes increase their expression of the gap junction channel subunit connexin 30, which in turn inhibits expression of a matrix-degrading enzyme (see the Perspective by Kofuji and Araque). As the matrix stabilizes, inhibitory interneurons mature, and the unusual flexibility of the critical period comes to an end. Science , abf5273, this issue p. 77 ; see also abj6745, p. 29
Published: 2021

46. Novel diffusion-weighted NMR tools for the characterization of tissue compartments in the rodent brain in vivo

Author: Vincent, Mélissa, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, and Julien Valette
Subjects: Diffusion, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], Lactate, In vivo NMR spectroscopy, Extracellular space, Spectroscopie RMN in vivo, Espace extracellulaire, Microstructure
Abstract: Neurodegenerative diseases lead to alterations in both cell microstructure (astrocytic hypertrophy, neuronal atrophy) and brain metabolism. The diffusion-weighted NMR signal reflects the environment locally explored by an ensemble of molecules at a microscopic scale, thus allowing to non-invasively probe brain microstructure. Diffusion imaging of water is therefore a promising method to better understand and diagnose neurodegenerative diseases. Besides, diffusion-weighted NMR spectroscopy could help clarifying the biodistribution within cell types of key molecules involved in brain metabolism, such as lactate. In the framework of the astrocyte-to-neuron lactate shuttle hypothesis, this information could indeed be crucial to elucidate the metabolic role of these molecules in both healthy and pathological conditions. The analysis of water diffusion data in terms of microstructure, or lactate diffusion data in terms of cell type distribution, however requires a precise knowledge of the diffusion properties within the different tissue compartments, in particular within the intracellular space (ICS) and the extracellular space (ECS). For example, is diffusion faster in ECS or ICS? Can diffusion in ECS be considered as free or is it sensitive to restriction and/or tortuosity? The goal of this work is to partly answer those questions. First, we study the sensitivity of double diffusion encoding (DDE) experiments to several features of cell microstructure, showing that the DDE signal of intracellular metabolites not only reflect diffusion in cell fibers, but also the presence of branching along those fibers. We then characterize the diffusion properties of sucrose, an exogenous marker of the ECS, using complementary diffusion-weighted NMR tools. These measurements allow us to capture several aspects of the ECS microstructure such as the apparent diffusion coefficient, tortuosity, restriction and microscopic anisotropy. Lastly, we explore the potential of an original approach using chemical exchange saturation transfer (CEST) to filter out the ICS contribution during water diffusion measurements. We conclude by mentioning how hyperpolarized ¹³C experiments could allow us to better characterize lactate diffusion properties within the different compartments.; Les maladies neurodégénératives sont caractérisées par des altérations de la microstructure cellulaire (hypertrophie astrocytaire, atrophie neuronale) ainsi que du métabolisme cérébral. Le signal RMN pondéré en diffusion reflète l’environnement exploré localement à l’échelle microscopique par un ensemble de molécules, constituant ainsi un outil de mesure non-invasif de la microstructure cérébrale. L’imagerie de diffusion de l’eau s’est donc imposée comme une approche prometteuse pour mieux comprendre et diagnostiquer les pathologies neurodégénératives. En outre, des mesures de spectroscopie pondérée en diffusion pourraient aider à clarifier la distribution au sein des différents types cellulaires de métabolites impliqués dans le métabolisme cérébral, tels que le lactate. Dans le contexte de l’hypothèse de la navette astrocyte-neurone, cette information est en effet cruciale afin d’éclaircir le rôle métabolique de ces molécules en conditions saine et pathologique. Cependant, l’analyse des données de diffusion de l’eau en termes de microstructure, ou bien des données de diffusion du lactate en termes de distribution cellulaire, suppose d’une part la connaissance précise des propriétés de diffusion au sein des différents compartiments tissulaires, en particulier les compartiments intracellulaires (ICS) et extracellulaire (ECS), et d’autre part que ces propriétés soient suffisamment différentes entre ces compartiments, afin de les discriminer. Par exemple, la diffusion est-elle plus rapide dans l’ECS ou l’ICS ? La diffusion dans l’ECS est-elle libre ou bien est-on au contraire sensible à des phénomènes de restriction et de tortuosité ? Le but de ce travail de thèse est de répondre en partie à ces questions. Dans un premier temps, nous étudions la sensibilité de la spectroscopie RMN à double encodage en diffusion (DDE) aux différents aspects de la microstructure cellulaire, montrant ainsi que le « signal » DDE des métabolites endogènes purement intracellulaire reflète non seulement la diffusion dans des prolongements cellulaire fibreux, mais aussi vraisemblablement la présence d’embranchements de ces prolongements cellulaires. Dans un second temps, nous caractérisons les propriétés de diffusion du sucrose, un marqueur exogène injecté dans l’ECS, grâce à des outils de spectroscopie RMN pondérée en diffusion permettant de collecter des informations complémentaires telles que le coefficient de diffusion apparent, la tortuosité, la restriction et l’anisotropie microscopique. Les mesures DDE se révèlent particulièrement à même de discriminer l’ECS et l’ICS. Enfin, nous explorons le potentiel d’une approche originale utilisant le transfert de saturation par échange chimique (CEST) afin de filtrer la contribution de l’ICS lors des mesures de diffusion. Pour conclure, nous évoquons comment des expériences de ¹³C hyperpolarisé pourraient permettre d’affiner la connaissance des propriétés de diffusion du lactate dans les différents compartiments.
Published: 2021

47. Astrocytes and neuropsychiatric symptoms in neurodegenerative diseases: Exploring the missing links

Author: Lucile Ben Haim, Carole Escartin, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Fondation pour la Recherche Medicale fellowship (ARF201909009244), Fondation Vaincre Alzheimer Pilot award (FR-20007p, 2021), France Alzheimer, ANR-20-CE16-0012,STERO-HD,Signalisation des stérols dans le striatum et effets protecteurs dans la Maladie de Huntington(2020), and ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011)
Subjects: Neurons, business.industry, General Neuroscience, Mental Disorders, cell-specific targeting, technology, industry, and agriculture, Context (language use), Cognition, Neurodegenerative Diseases, Disease, depressive-like symptoms, animal models, Astrocytes, Medicine, Humans, In patient, behavioral tests, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], neuronal networks, business, Neuroscience, Neuron-astrocyte interactions
Abstract: International audience; Neurodegenerative diseases (ND) are characterized by primary symptoms such as cognitive or motor deficits. In addition, the presence of neuropsychiatric symptoms (NPS) in ND patients is being increasingly acknowledged as an important disease feature. Yet, their neurobiological basis remains unclear and mostly centered on neurons while overlooking astrocytes, which are crucial regulators of neuronal function underlying complex behaviors. In this opinion article, we briefly review evidence for NPS in ND and discuss their experimental assessment in preclinical models. We then present recent studies showing that astrocyte-specific dysfunctions can lead to NPS. Because many astrocyte alterations are also observed in ND, we suggest that they might underlie NDassociated NPS. We argue that there is a need for dedicated preclinical studies assessing astrocytebased therapeutic strategies targeting NPS in the context of ND.
Published: 2021

48. Novel diffusion-weighted NMR tools for the characterization of tissue compartments in the rodent brain in vivo

Author: Vincent, Mélissa, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Julien Valette, STAR, ABES, Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: Diffusion, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [PHYS.PHYS.PHYS-MED-PH] Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Lactate, In vivo NMR spectroscopy, Extracellular space, Spectroscopie RMN in vivo, Espace extracellulaire, Microstructure
Abstract: Neurodegenerative diseases lead to alterations in both cell microstructure (astrocytic hypertrophy, neuronal atrophy) and brain metabolism. The diffusion-weighted NMR signal reflects the environment locally explored by an ensemble of molecules at a microscopic scale, thus allowing to non-invasively probe brain microstructure. Diffusion imaging of water is therefore a promising method to better understand and diagnose neurodegenerative diseases. Besides, diffusion-weighted NMR spectroscopy could help clarifying the biodistribution within cell types of key molecules involved in brain metabolism, such as lactate. In the framework of the astrocyte-to-neuron lactate shuttle hypothesis, this information could indeed be crucial to elucidate the metabolic role of these molecules in both healthy and pathological conditions. The analysis of water diffusion data in terms of microstructure, or lactate diffusion data in terms of cell type distribution, however requires a precise knowledge of the diffusion properties within the different tissue compartments, in particular within the intracellular space (ICS) and the extracellular space (ECS). For example, is diffusion faster in ECS or ICS? Can diffusion in ECS be considered as free or is it sensitive to restriction and/or tortuosity? The goal of this work is to partly answer those questions. First, we study the sensitivity of double diffusion encoding (DDE) experiments to several features of cell microstructure, showing that the DDE signal of intracellular metabolites not only reflect diffusion in cell fibers, but also the presence of branching along those fibers. We then characterize the diffusion properties of sucrose, an exogenous marker of the ECS, using complementary diffusion-weighted NMR tools. These measurements allow us to capture several aspects of the ECS microstructure such as the apparent diffusion coefficient, tortuosity, restriction and microscopic anisotropy. Lastly, we explore the potential of an original approach using chemical exchange saturation transfer (CEST) to filter out the ICS contribution during water diffusion measurements. We conclude by mentioning how hyperpolarized ¹³C experiments could allow us to better characterize lactate diffusion properties within the different compartments., Les maladies neurodégénératives sont caractérisées par des altérations de la microstructure cellulaire (hypertrophie astrocytaire, atrophie neuronale) ainsi que du métabolisme cérébral. Le signal RMN pondéré en diffusion reflète l’environnement exploré localement à l’échelle microscopique par un ensemble de molécules, constituant ainsi un outil de mesure non-invasif de la microstructure cérébrale. L’imagerie de diffusion de l’eau s’est donc imposée comme une approche prometteuse pour mieux comprendre et diagnostiquer les pathologies neurodégénératives. En outre, des mesures de spectroscopie pondérée en diffusion pourraient aider à clarifier la distribution au sein des différents types cellulaires de métabolites impliqués dans le métabolisme cérébral, tels que le lactate. Dans le contexte de l’hypothèse de la navette astrocyte-neurone, cette information est en effet cruciale afin d’éclaircir le rôle métabolique de ces molécules en conditions saine et pathologique. Cependant, l’analyse des données de diffusion de l’eau en termes de microstructure, ou bien des données de diffusion du lactate en termes de distribution cellulaire, suppose d’une part la connaissance précise des propriétés de diffusion au sein des différents compartiments tissulaires, en particulier les compartiments intracellulaires (ICS) et extracellulaire (ECS), et d’autre part que ces propriétés soient suffisamment différentes entre ces compartiments, afin de les discriminer. Par exemple, la diffusion est-elle plus rapide dans l’ECS ou l’ICS ? La diffusion dans l’ECS est-elle libre ou bien est-on au contraire sensible à des phénomènes de restriction et de tortuosité ? Le but de ce travail de thèse est de répondre en partie à ces questions. Dans un premier temps, nous étudions la sensibilité de la spectroscopie RMN à double encodage en diffusion (DDE) aux différents aspects de la microstructure cellulaire, montrant ainsi que le « signal » DDE des métabolites endogènes purement intracellulaire reflète non seulement la diffusion dans des prolongements cellulaire fibreux, mais aussi vraisemblablement la présence d’embranchements de ces prolongements cellulaires. Dans un second temps, nous caractérisons les propriétés de diffusion du sucrose, un marqueur exogène injecté dans l’ECS, grâce à des outils de spectroscopie RMN pondérée en diffusion permettant de collecter des informations complémentaires telles que le coefficient de diffusion apparent, la tortuosité, la restriction et l’anisotropie microscopique. Les mesures DDE se révèlent particulièrement à même de discriminer l’ECS et l’ICS. Enfin, nous explorons le potentiel d’une approche originale utilisant le transfert de saturation par échange chimique (CEST) afin de filtrer la contribution de l’ICS lors des mesures de diffusion. Pour conclure, nous évoquons comment des expériences de ¹³C hyperpolarisé pourraient permettre d’affiner la connaissance des propriétés de diffusion du lactate dans les différents compartiments.
Published: 2021

49. Suppression of $\alpha$-synuclein propagation after intrastriatal injection in FABP3 null mice

Author: Ichiro Kawahata, Kohji Fukunaga, Ronald Melki, Luc Bousset, Yuji Owada, Kazuya Matsuo, Tohoku University [Sendai], Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), School of Engineering [Tohoku Univ], and Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB)
Subjects: 0301 basic medicine, Male, Synucleinopathies, Parkinson's disease, [SDV]Life Sciences [q-bio], ventral tegmental area, Substantia nigra, Striatum, macromolecular substances, Fibril, 03 medical and health sciences, Mice, 0302 clinical medicine, α-synuclein, tyrosine hydroxylase, medicine, Animals, substantia nigra pars compacta, fatty acid-binding protein, Molecular Biology, Pars Compacta, Mice, Knockout, Pars compacta, Chemistry, phosphorylated αSyn, General Neuroscience, Dopaminergic Neurons, Dopaminergic, Neurotoxicity, medicine.disease, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, Lewy body, Lewy neurite, alpha-Synuclein, Neurology (clinical), dementia with Lewy bodies, Fatty Acid Binding Protein 3, 030217 neurology & neurosurgery, Intracellular, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology
Abstract: International audience; Accumulation and aggregation of α-synuclein (αSyn) trigger neuronal loss in the substantia nigra pars compacta (SNpc), which in turn causes motor symptoms in Parkinson's disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3), an intracellular fatty acid carrier protein, enhances αSyn neurotoxicity in SNpc and motor impairments after intranigral injection of αSyn fibrils. However, the temporal profile of αSyn fibril spread and their toxicity remains unclear. In the present study, we investigated the temporal profile of αSyn fibril spread and its toxicity, which induces intracellular fibril formation. Monomeric and fibrillar aSyn assemblies were labeled with ATTO550 to distinguish the exogenous form from the endogenous species and injected into bilateral striatum in Fabp3$^{+/+}$ (wild type) and Fabp3$^{-/-}$ mice. Accumulation of both monomeric and fibrillar exogenous αSyn in the SNpc was drastically decreased in Fabp$^{-/-}$mice compared to that in the Fabp3$^{+/+}$ counterparts. Deletion of Fabp3 also prevented exogenous αSyn fibril-induced seeding of the endogenous αSyn into aggregates containing phosphorylated and filamentous forms in the SNpc. Consistent with these results, loss of dopaminergic neurons and subsequent impaired motor behavior were attenuated in Fabp3$^{-/-}$ mice. These results highlight the crucial role of FABP3 in pathogenic αSyn accumulation and its seeding ability. Taken together, FABP3 could be a potential therapeutic target against αSyn propagation in synucleinopathies.
Published: 2021

50. Role of DNA Repair Variants and Diagnostic Radiology Exams in Differentiated Thyroid Cancer Risk: A Pooled Analysis of Two Case–Control Studies

Author: Carole Rubino, Pascal Guénel, Emilie Cordina-Duverger, Françoise Borson-Chazot, Vincent Souchard, Pierre Laurent-Puig, Florent de Vathaire, Thérèse Truong, Julie Guibon, Anne-Valérie Guizard, Mojgan Karimi, Elizabeth Adjadj, Catherine Ory, Hélène Blanché, Jean-Baptiste Cazier, Sylvie Chevillard, Martin Schlumberger, Constance Xhaard, Claire Schvartz, Yan Ren, Fabienne Lesueur, Jean-François Deleuze, Anne Boland, Mohammed Zakarya Zemmache, Sandra Canale, Eugènia Mariné Barjoan, Claire Mulot, Monia Zidane, Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Université Paris-Saclay, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), Laboratory of Excellence GENMED (Medical Genomics), Laboratoire de Cancérologie Expérimentale (LCE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Service de Radobiologie Expérimentale et Innovation Technologique (SREIT), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Jean Godinot [Reims], UNICANCER, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Epigenetec, Centre de Ressources Biologiques (CRB), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Paris 5 (UPD5), University of Birmingham [Birmingham], FDV received the following grants as principal investigator of Young-Thyr study: Fondation de France (Grant number 65391), L'Alliance pour les sciences de la vie et de la santé, « AVIESAN » (Grants number ENV201416 and 2007005070), the Ligue Nationale Contre le Cancer (LNCC) (Grants number EPDAC6036, EPDTP6004, R10127LL).TT received the following grants for CATHY 470 and Young-Thyr studies genotyping Institut National du Cancer (Grant number 9533), the ARC foundation (Grant number PGA120150202302) MZ performed this work during her PhD funded by Ecole des Hautes Etudes en Santé Publique (EHESP) and the ARC Foundation (Grant number ARCDOC42020070002532)., Université Paris Sud Orsay, Inserm, U900, Institut Curie, Université PSL, Mines ParisTech, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, and BOZEC, Erwan
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Neoplasms, Radiation-Induced, Adolescent, DNA Repair, Epidemiology, DNA repair, Thyroid Gland, Single-nucleotide polymorphism, Logistic regression, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, Young Adult, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Genetic predisposition, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Thyroid Neoplasms, Child, Thyroid cancer, Aged, Aged, 80 and over, business.industry, Thyroid, Case-control study, Dose-Response Relationship, Radiation, Middle Aged, medicine.disease, Confidence interval, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Radiology, France, business
Abstract: Background: Given the increased use and diversity of diagnostic procedures, it is important to understand genetic susceptibility to radiation-induced thyroid cancer. Methods: On the basis of self-declared diagnostic radiology examination records in addition to existing literature, we estimated the radiation dose delivered to the thyroid gland from diagnostic procedures during childhood and adulthood in two case–control studies conducted in France. A total of 1,071 differentiated thyroid cancer (DTC) cases and 1,188 controls from the combined studies were genotyped using a custom-made Illumina OncoArray DNA chip. We focused our analysis on variants in genes involved in DNA damage response and repair pathways, representing a total of 5,817 SNPs in 571 genes. We estimated the OR per milli-Gray (OR/mGy) of the radiation dose delivered to the thyroid gland using conditional logistic regression. We then used an unconditional logistic regression model to assess the association between DNA repair gene variants and DTC risk. We performed a meta-analysis of the two studies. Results: The OR/mGy was 1.02 (95% confidence interval, 1.00–1.03). We found significant associations between DTC and rs7164173 in CHD2 (P = 5.79 × 10−5), rs6067822 in NFATc2 (P = 9.26 × 10−5), rs1059394 and rs699517 both in ENOSF1/THYS, rs12702628 in RPA3, and an interaction between rs7068306 in MGMT and thyroid radiation doses (P = 3.40 × 10−4). Conclusions: Our results suggest a role for variants in CDH2, NFATc2, ENOSF1/THYS, RPA3, and MGMT in DTC risk. Impact: CDH2, NFATc2, ENOSF1/THYS, and RPA3 have not previously been shown to be associated with DTC risk.
Published: 2021

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