Descriptor: "MESH: Alzheimer Disease" - Searchworks@Jio Institute Digital Library Search Results

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139 results on '"MESH: Alzheimer Disease"'

1. Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic Aβ Peptides

Author: Linda Hanbouch, Béatrice Schaack, Amal Kasri, Gaëlle Fontaine, Eleni Gkanatsiou, Gunnar Brinkmalm, Elena Camporesi, Erik Portelius, Kaj Blennow, Gilles Mourier, Nicolas Gilles, Mark J. Millan, Catherine Marquer, Henrik Zetterberg, Lydie Boussicault, Marie-Claude Potier, 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), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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 Grenoble Alpes (UGA), Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, 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), Center for Innovation in Neuropsychiatry, Institut de Recherches Servier, Croissy sur Seine, France., DLS platforms of the Grenoble Instruct-ERIC center (ISBG, UMS 3518 CNRS-CEA-UGA-EMBL), Thomas, Frank, and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: MESH: Amino Acids, MESH: Mutation, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Neuroscience (miscellaneous), Amyloid beta-Protein Precursor, Cellular and Molecular Neuroscience, MESH: Cholesterol, Alzheimer Disease, MESH: Amyloid beta-Protein Precursor, mental disorders, Humans, Amino Acids, Aβ, Amyloid beta-Peptides, Binding Sites, MESH: Humans, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Mutant, MESH: Amyloid beta-Peptides, HEK293 Cells, Cholesterol, Neurology, MESH: Amyloid Precursor Protein Secretases, MESH: Binding Sites, Amyloid precursor protein, MESH: HEK293 Cells, Mutation, Amyloid Precursor Protein Secretases, Alzheimer’s disease, MESH: Alzheimer Disease
Abstract: Excess brain cholesterol is strongly implicated in the pathogenesis of Alzheimer disease (AD). Here we evaluated how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of the amyloid precursor protein (APP) regulates its processing.We generated nine point mutations in the APP gene, changing the charge and/or hydrophobicity of the amino-acids which were previously shown as part of the CBS. Most mutations triggered a reduction of amyloid-β peptides Aβ40 and Aβ42 secretion from transfected HEK293T cells. Only the K to A mutation at position 28 of Aβ in the APP sequence (APPK28A) resulted in a concomitant increase in the production of shorter Aβ peptides. Mass Spectrometry (MS) confirmed the predominance of Aβx-33 and Aβx-34. The enzymatic activity of α-, β- and g-secretases remained unchanged in cells expressing the APPK28A and all other mutants. Similarly, subcellular localization of the mutants in early endosomes did not differ from the APPWT protein. A transient increase of plasma membrane cholesterol enhanced the production of Aβ40 and Aβ42 by APPWT, an effect absent in APPK28A mutant. Finally, WT but not CBS mutant Aβ derived peptides bound to cholesterol-rich exosomes. Collectively, the present data revealed a major role of juxtamembrane amino acids of the APP CBS in modulating the production of toxic Aβ species. More generally, they underpin the role of cholesterol in the pathophysiology of AD.
Published: 2022

2. A shared disease-associated oligodendrocyte signature among multiple CNS pathologies

Author: Kenigsbuch, Mor, Bost, Pierre, Halevi, Shahar, Chang, Yuzhou, Chen, Shuo, Ma, Qin, Hajbi, Renana, Schwikowski, Benno, Bodenmiller, Bernd, Fu, Hongjun, Schwartz, Michal, Amit, Ido, University of Zurich, Schwartz, Michal, Amit, Ido, Weizmann Institute of Science [Rehovot, Israël], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ecole Doctorale Complexité du Vivant (ED515), Sorbonne Université (SU), Universität Zürich [Zürich] = University of Zurich (UZH), Ohio State University [Columbus] (OSU), The research of I.A. is supported by the Seed Networks for the Human Cell Atlas of the Chan Zuckerberg Initiative, the Thompson Family Foundation Alzheimer’s Research Fund and the Adelis Foundation. I.A. is an Eden and Steven Romick Professorial Chair, supported by the HHMI International Scholar Award, a European Research Council Consolidator Grant (724471-HemTree2.0), an MRA Established Investigator Award (509044), the DFG (SFB/TRR167), the Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine, the Helen and Martin Kimmel awards for innovative investigation and the SCA award of the Wolfson Foundation and Family Charitable Trust. Research in the M.S. laboratory is supported by Advanced European Research Council grants (741744), Israel Science Foundation (ISF) research grant 991/16, and and ISF-Legacy Heritage Bio-Medical Science Partnership research grant 1354/15. We would like to thank the Adelis and Thompson Foundations for their generous support of our AD research. This work is also supported by awards K01-AG056673 and R56-066782–01 from the National Institute on Aging of the National Institutes of Health, R01-GM131399 (Q.M.) from the National Institute of General Medical Sciences, AARF-17–505009 (H.F.) from the Alzheimer’s Association and W81XWH1910309 (H.F.) from the US Department of Defense.
Subjects: MESH: Mice, Transgenic, Mice, Transgenic, Plaque, Amyloid, 610 Medicine & health, Article, MESH: Neurodegenerative Diseases, MESH: Brain, Amyloid beta-Protein Precursor, Mice, Alzheimer Disease, MESH: Amyloid beta-Protein Precursor, Animals, Humans, MESH: Animals, MESH: Mice, MESH: Humans, Amyloid beta-Peptides, [SCCO.NEUR]Cognitive science/Neuroscience, General Neuroscience, Brain, 2800 General Neuroscience, MESH: Oligodendroglia, Neurodegenerative Diseases, MESH: Amyloid beta-Peptides, MESH: Plaque, Amyloid, Disease Models, Animal, Oligodendroglia, MESH: Disease Models, Animal, 11493 Department of Quantitative Biomedicine, MESH: Alzheimer Disease
Abstract: Alzheimer’s disease (AD) is a complex neurodegenerative disease, perturbing neuronal and non-neuronal cell populations. In this study, using single-cell transcriptomics, we mapped all non-immune, non-neuronal cell populations in wild-type and AD model (5xFAD) mouse brains. We identified an oligodendrocyte state that increased in association with brain pathology, which we termed disease-associated oligodendrocytes (DOLs). In a murine model of amyloidosis, DOLs appear long after plaque accumulation, and amyloid-beta (Aβ) alone was not sufficient to induce the DOL signature in vitro. DOLs could be identified in a mouse model of tauopathy and in other murine neurodegenerative and autoimmune inflammatory conditions, suggesting a common response to severe pathological conditions. Using quantitative spatial analysis of mouse and postmortem human brain tissues, we found that oligodendrocytes expressing a key DOL marker (SERPINA3N/SERPINA3 accordingly) are present in the cortex in areas of brain damage and are enriched near Aβ plaques. In postmortem human brain tissue, the expression level of this marker correlated with cognitive decline. Altogether, this study uncovers a shared signature of oligodendrocytes in central nervous system pathologies., Nature Neuroscience, 25 (7), ISSN:1097-6256, ISSN:1546-1726
Published: 2022
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3. 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

4. Dynamic reciprocal relationships between cognitive and functional declines along the Alzheimer’s disease continuum in the prospective COGICARE study

Author: Sophie Carles, Bachirou O. Taddé, Claudine Berr, Catherine Helmer, Hélène Jacqmin-Gadda, Isabelle Carrière, Cécile Proust-Lima, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité Mixte de Recherche d'Épidémiologie des maladies Animales et zoonotiques (UMR EPIA), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier (INM), and Proust-Lima, Cécile
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, MESH: Cognition, Neuropsychological Tests, MESH: Cognitive Dysfunction, Cognitive aging, Cognition, [STAT.AP] Statistics [stat]/Applications [stat.AP], Alzheimer Disease, Humans, Cognitive Dysfunction, Prospective Studies, RC346-429, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Humans, Research, MESH: Activities of Daily Living, Activities of daily living, MESH: Neuropsychological Tests, MESH: Prospective Studies, Causality, Temporal association, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Mini-Mental State Examination, Dementia, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology. Diseases of the nervous system, MESH: Alzheimer Disease, RC321-571
Abstract: Background Thoroughly understanding the temporal associations between cognitive and functional dimensions along the dementia process is fundamental to define preventive measures likely to delay the disease’s onset. This work aimed to finely describe the trajectories of cognitive and functional declines, and assess their dynamic bidirectional relationships among subjects at different stages of the dementia process. Methods We leveraged extensive repeated data of cognition and functional dependency from the French prospective COGICARE study, designed to better characterize the natural history of cognitive and functional declines around dementia diagnosis. Cognition was measured by the Mini-Mental State Examination, the Isaacs Set Test for verbal fluency, the Benton Visual Retention Test for visuo-spatial memory, and Trail Making Test Part B for executive functioning. Functional dependency was measured by basic and instrumental activities of daily living. The study included 102 cognitively normal, 123 mildly cognitively impaired, and 72 dementia cases with a median of 5 repeated visits over up to 57 months. We used a dynamic causal model which addresses the two essential issues in temporal associations assessment: focusing on intra-individual change and accounting for time. Results Better cognitive abilities were associated with lower subsequent decline of the functional level among the three clinical stages with an intensification over time but no reciprocity of the association whatever the clinical status. Conclusion This work confirms that the progressive functional dependency could be induced by cognitive impairment. Subjects identified as early as possible with clinically significant cognitive impairments could benefit from preventive measures before the deterioration of activities of daily living and the appearance of dementia clinical signs. Supplementary Information The online version contains supplementary material available at 10.1186/s13195-021-00887-4.
Published: 2021

5. Phosphorylated tau181 in plasma as a potential biomarker for Alzheimer’s disease in adults with Down syndrome

Author: Kaj Blennow, Sylvain Lehmann, Nicholas J. Ashton, Jordi Pegueroles, Rafael Blesa, Maria Florencia Iulita, Alberto Lleó, Miren Altuna, Valle Camacho, Henrik Zetterberg, Maria Carmona-Iragui, Daniel Alcolea, Diana Garzón, Susana Fernández, Juan Lantero-Rodriguez, Santiago Medrano-Martorell, Juan Fortea, Jordi Clarimón, Thomas K. Karikari, Olivia Belbin, Alexandre Bejanin, Laura Videla, Sílvia Valldeneu, Bessy Benejam, Isabel Barroeta, Victor Montal, Hospital de la Santa Creu i Sant Pau, Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Universitat Autònoma de Barcelona (UAB), Sahlgrenska Academy at University of Gothenburg [Göteborg], Sahlgrenska University Hospital [Gothenburg], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), Institute of Neurology [London], Fundació Catalana de Síndrome de Down [Barcelona], University of Gothenburg (GU), King‘s College London, IMIM-Hospital del Mar, Generalitat de Catalunya, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Herrada, Anthony
Subjects: Male, 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Physics and Astronomy, MESH: Cognition, Disease, Gastroenterology, Cognition, 0302 clinical medicine, Neurofilament Proteins, Medicine, Phosphorylation, MESH: Neurofilament Proteins, Cerebral Cortex, education.field_of_study, MESH: Middle Aged, Multidisciplinary, Area under the curve, Middle Aged, Alzheimer's disease, MESH: Amyloid beta-Peptides, MESH: tau Proteins, Area Under Curve, Disease Progression, Biomarker (medicine), MESH: Disease Progression, Female, medicine.symptom, Adult, medicine.medical_specialty, Down syndrome, Science, Population, tau Proteins, MESH: Atrophy, Predictive markers, Asymptomatic, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Cross-Sectional Studies, Atrophy, Alzheimer Disease, Internal medicine, Humans, Dementia, education, MESH: Humans, Amyloid beta-Peptides, MESH: Phosphorylation, business.industry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Adult, MESH: Down Syndrome, General Chemistry, medicine.disease, MESH: Cerebral Cortex, MESH: Male, Cross-Sectional Studies, 030104 developmental biology, MESH: Biomarkers, MESH: Area Under Curve, Down Syndrome, business, MESH: Female, MESH: Alzheimer Disease, Biomarkers, 030217 neurology & neurosurgery
Abstract: Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73–0.87] and 0.92 [95% CI 0.89–0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS., Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology. Here, the authors investigated whether plasma ptau181 could be a potential biomarker of AD in individuals with Down syndrome (DS) and find plasma p-tau181 can detect AD in DS adults.
Published: 2021

6. Aptamarker prediction of brain amyloid-β status in cognitively normal individuals at risk for Alzheimer’s disease

Author: Penner, G, Lecocq, S, Chopin, A, Vedoya, X, Lista, S, Vergallo, A, Cavedo, E, Lejeune, F, Dubois, B, Hampel, H, Bakardjian, H, Benali, H, Bertin, H, Bonheur, J, Boukadida, L, Boukerrou, N, Chiesa, Pa, Colliot, O, Dubois, M, Epelbaum, S, Gagliardi, G, Genthon, R, Habert, M, Houot, M, Kas, A, Lamari, F, Levy, M, Metzinger, C, Mochel, F, Nyasse, F, Poisson, C, Potier, M, Revillon, M, Santos, A, Andrade, Ks, Sole, M, Surtee, M, de Schotten, Mt, Younsi, N, Afshar, M, Aguilar, Lf, Akman-Anderson, L, Aremas, J, Avila, J, Babiloni, C, Baldacci, F, Batrla, R, Benda, N, Black, Kl, Bokde, Alw, Bonuccelli, U, Broich, K, Cacciola, F, Caraci, F, Caruso, G, Castrillo, J, Ceravolo, R, Corbo, M, Corvol, J, Cuello, Ac, Cummings, Jl, Depypere, H, Duggento, A, Emanuele, E, Escott-Price, V, Federoff, H, Ferretti, Mt, Fiandaca, M, Frank, Ra, Garaci, F, Geerts, H, Giacobini, E, Giorgi, Fs, Goetzl, Ej, Graziani, M, Haberkamp, M, Hanisch, B, Herholz, K, Hernandez, F, Imbimbo, Bp, Kapogiannis, D, Karran, E, Kiddle, Sj, Kim, Sh, Koronyo, Y, Koronyo-Hamaoui, M, Langevin, T, Lehericy, S, Lemercier, P, Llavero, F, Lorenceau, J, Lucia, A, Mango, D, Mapstone, M, Neri, C, Nistico, R, O'Bryant, Se, Palermo, G, Perry, G, Ritchie, C, Rossi, S, Saidi, A, Santarnecchi, E, Schneider, Ls, Sporns, O, Toschi, N, Valenzuela, Pl, Vellas, B, Verdooner, Sr, Villain, N, Giudici, Kv, Watling, M, Welikovitch, La, Woodcock, J, Younesi, E, Zugaza, Jl, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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), 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), and Gasset, Maria
Subjects: Male, Aging, Amyloid β, MESH: SELEX Aptamer Technique, [SDV]Life Sciences [q-bio], Oligonucleotides, Artificial Gene Amplification and Extension, Disease, Neurodegenerative, Alzheimer's Disease, Pathology and Laboratory Medicine, Biochemistry, Polymerase Chain Reaction, Diagnostic Radiology, Negative selection, Medical Conditions, Mathematical and Statistical Techniques, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Early Diagnosis, 80 and over, Medicine and Health Sciences, Biomarker discovery, Tomography, Aged, 80 and over, MESH: Aged, screening and diagnosis, 0303 health sciences, Multidisciplinary, Nucleotides, Mathematical Models, Radiology and Imaging, SELEX Aptamer Technique, Settore MED/37 - Neuroradiologia, Neurodegenerative Diseases, MESH: Case-Control Studies, MESH: Amyloid beta-Peptides, Detection, Neurology, Neurological, Medicine, Biomedical Imaging, Female, Biotechnology, 4.2 Evaluation of markers and technologies, Research Article, Amyloid, General Science & Technology, Imaging Techniques, Science, Aptamer, Neuroimaging, and over, Computational biology, Biology, Research and Analysis Methods, 03 medical and health sciences, Clinical Research, Diagnostic Medicine, Alzheimer Disease, Mental Health and Psychiatry, Acquired Cognitive Impairment, Humans, Risk factor, Molecular Biology Techniques, Molecular Biology, Aged, 030304 developmental biology, Amyloid beta-Peptides, MESH: Humans, Prevention, Neurosciences, Alzheimer Precision Medicine Initiative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biology and Life Sciences, Omics, MESH: Male, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, Early Diagnosis, Case-Control Studies, MESH: Biomarkers, Dementia, INSIGHT-preAD study group, MESH: Female, Biomarkers, Positron Emission Tomography, 030217 neurology & neurosurgery, MESH: Alzheimer Disease, Neuroscience
Abstract: International audience; The traditional approach to biomarker discovery for any pathology has been through hypothesis-based research one candidate at a time. The objective of this study was to develop an agnostic approach for the simultaneous screening of plasma for consistent molecular differences between a group of individuals exhibiting a pathology and a group of healthy individuals. To achieve this, we focused on developing a predictive tool based on plasma for the amount of brain amyloid-β deposition as observed in PET scans. The accumulation of brain amyloid-β (Aβ) plaques is a key risk factor for the development of Alzheimer's disease. A contrast was established between cognitively normal individuals above the age of 70 that differed for the amount of brain amyloid-β observed in PET scans (INSIGHT study group). Positive selection was performed against a pool of plasma from individuals with high brain amyloid and negative selection against a pool of plasma from individuals with low brain amyloid This enriched, selected library was then applied to plasma samples from 11 individuals with high levels of brain amyloid and 11 individuals with low levels of brain Aβ accumulation. Each of these individually selected libraries was then characterized by next generation sequencing, and the relative frequency of 10,000 aptamer sequences that were observed in each selection was screened for ability to explain variation in brain amyloid using sparse partial least squares discriminant analysis. From this analysis a subset of 44 aptamers was defined, and the individual aptamers were synthesized. This subset was applied to plasma samples from 70 cognitively normal individuals all above the age of 70 that differed for brain amyloid deposition. 54 individuals were used as a training set, and 15 as a test set. Three of the 15 individuals in the test set were mis-classified resulting in an overall accuracy of 80% with 86% sensitivity and 75% specificity. The aptamers included in the subset serve directly as biomarkers, thus we have named them Aptamarkers. There are two potential applications of these results: extending the predictive capacity of these aptamers across a broader range of individuals, and/or using the individual aptamers to identify targets through covariance analysis and reverse omics approaches. We are currently expanding applications of the Aptamarker platform to other diseases and target matrices.
Published: 2021

7. Hypocretin/Orexin, Sleep and Alzheimer’s Disease

Author: Yves Dauvilliers, Salvy-Córdoba, Nathalie, Michel A. Steiner, Masashi Yanagisawa, Martine Clozel, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Sleep Wake Disorders, MESH: Orexins, MESH: Glymphatic System, Translational research, tau Proteins, Disease, Pathogenesis, MESH: Tau Proteins, Alzheimer Disease, MESH: Narcolepsy, Medicine, Animals, Humans, MESH: Animals, Circadian rhythm, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive decline, Narcolepsy, Orexins, Amyloid beta-Peptides, MESH: Humans, business.industry, Sleep in non-human animals, MESH: Amyloid beta-Peptides, MESH: Sleep Wake Disorders, Biomarker (medicine), Wakefulness, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, Neuroscience, Glymphatic System, MESH: Alzheimer Disease
Abstract: International audience; Advances in translational research provide key opportunities to explore the physiological and pathological effects of sleep in different neurodegenerative diseases. Recent findings suggest that sleep-wakefulness dysfunctions may predispose to neurodegenerative disorders such as Alzheimer's disease (AD), and vice versa. New theories on the link between sleep and β-amyloid and tau secretion, accumulation and clearance, and its interaction with hypocretins/orexins (key neuropeptides regulating wakefulness) suggest mechanistic ways to better understand the impact of sleep alterations in the pathogenesis of AD. Further studies should validate whether changes in circadian rhythm and sleep-wakefulness patterns could be used for early AD diagnosis and as prognostic markers for cognitive decline. Longitudinal studies are needed, not only to validate these biomarker interactions and to determine the cause-effect relationship and the role of sleep-wakefulness behavior in the regulation of amyloid plaque and neurofibrillary tangle formation, but also to identify the best sleep therapies and related preventive strategies for AD.
Published: 2021

8. Age and sex impact plasma NFL and t-Tau trajectories in individuals with subjective memory complaints: a 3-year follow-up study

Author: Baldacci, F., Lista, S., Manca, M. L., Chiesa, P. A., Cavedo, E., Lemercier, P., Zetterberg, H., Blennow, K., Habert, M. -O., Potier, M. C., Dubois, B., Vergallo, A., Hampel, H., Bakardjian, H., Benali, H., Bertin, H., Bonheur, J., Boukadida, L., Boukerrou, N., Chiesa, P., Colliot, O., Dubois, M., Epelbaum, S., Gagliardi, G., Genthon, R., Houot, M., Kas, A., Lamari, F., Levy, M., Metzinger, C., Mochel, F., Nyasse, F., Poisson, C., Potier, M. -C., Revillon, M., Santos, A., Andrade, K. S., Sole, M., Surtee, M., de Schotten, M. T., Younsi, N., Afshar, M., Aguilar, L. F., Akman-Anderson, L., Arenas, J., Avila, J., Babiloni, C., Batrla, R., Benda, N., Black, K. L., Bokde, A. L. W., Bonuccelli, U., Broich, K., Cacciola, F., Caraci, F., Caruso, G., Castrillo, J., Ceravolo, R., Corbo, M., Corvol, J. -C., Claudio, A., Cummings, J. L., Depypere, H., Duggento, A., Emanuele, E., Escott-Price, V., Federoff, H., Ferretti, M. T., Fiandaca, M., Frank, R. A., Garaci, F., Geerts, H., Giacobini, E., Giorgi, F. S., Goetzl, E. J., Graziani, M., Haberkamp, M., Hanisch, B., Herholz, K., Hernandez, F., Imbimbo, B. P., Kapogiannis, D., Karran, E., Kiddle, S. J., Kim, S. H., Koronyo, Y., Koronyo-Hamaoui, M., Langevin, T., Lehericy, S., Llavero, F., Lorenceau, J., Lucia, A., Mango, D., Mapstone, M., Neri, C., Nistico, R., O'Bryant, S. E., Palermo, G., Perry, G., Ritchie, C., Rossi, S., Saidi, A., Santarnecchi, E., Schneider, L. S., Sporns, O., Toschi, N., Valenzuela, P. L., Vellas, B., Verdooner, S. R., Villain, N., Virecoulon Giudici, K., Watling, M., Welikovitch, L. A., Woodcock, J., Younesi, E., Zugaza, J. L., Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), 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), University of Pisa - Università di Pisa, 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], 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), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Sahlgrenska Academy at University of Gothenburg [Göteborg], University College of London [London] (UCL), UK Dementia Research Institute (UK DRI), 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), Service de médecine nucléaire [CHU Pitié-Salpétrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, BIOMARKER, 0301 basic medicine, Oncology, Aging, Neurology, [SDV]Life Sciences [q-bio], Disease, Neurodegenerative, Alzheimer's Disease, Medical and Health Sciences, lcsh:RC346-429, MESH: Cognitive Dysfunction, Alzheimer’s disease, Biomarkers, Mild cognitive impairment, Neurofilament light chain, Subjective memory complainers, Tau, 0302 clinical medicine, Neurofilament Proteins, Medicine and Health Sciences, BRAIN, MESH: Neurofilament Proteins, RISK, Settore FIS/07, NEURODEGENERATION, Cognition, ASSOCIATION, MESH: Follow-Up Studies, Alzheimer's disease, MESH: Amyloid beta-Peptides, MESH: tau Proteins, ALZHEIMERS-DISEASE, POSITIVITY, Neurological, Cohort, Biomarker (medicine), Female, medicine.medical_specialty, Cognitive Neuroscience, tau Proteins, Subjective, Affect (psychology), VALIDATION, lcsh:RC321-571, subjective memory complainers, mild cognitive impairment, biomarkers, s disease, 03 medical and health sciences, memory complainers, Clinical Research, Alzheimer Disease, Internal medicine, NEUROFILAMENT LIGHT-CHAIN, Acquired Cognitive Impairment, medicine, Humans, Cognitive Dysfunction, Vitamin B12, Allele, Alzheimer&#8217, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, Amyloid beta-Peptides, MESH: Humans, business.industry, Research, Prevention, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer Precision Medicine Initiative, COGNITIVE IMPAIRMENT, MESH: Male, Brain Disorders, 030104 developmental biology, MESH: Biomarkers, Dementia, Neurology (clinical), business, INSIGHT-preAD study group, MESH: Female, MESH: Alzheimer Disease, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Background Plasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer’s disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE ε4 allele, comorbidities, brain amyloid-β (Aβ) burden, and cognitive scores on plasma NFL and t-Tau concentrations in cognitively healthy individuals with SMC, a condition associated with AD development. Methods Three hundred sixteen and 79 individuals, respectively, have baseline and three-time point assessments (at baseline, 1-year, and 3-year follow-up) of the two biomarkers. Plasma biomarkers were measured with an ultrasensitive assay in a mono-center cohort (INSIGHT-preAD study). Results We show an effect of age on plasma NFL, with women having a higher increase of plasma t-Tau concentrations compared to men, over time. The APOE ε4 allele does not affect the biomarker concentrations while plasma vitamin B12 deficiency is associated with higher plasma t-Tau concentrations. Both biomarkers are correlated and increase over time. Baseline NFL is related to the rate of Aβ deposition at 2-year follow-up in the left-posterior cingulate and the inferior parietal gyri. Baseline plasma NFL and the rate of change of plasma t-Tau are inversely associated with cognitive score. Conclusion We find that plasma NFL and t-Tau longitudinal trajectories are affected by age and female sex, respectively, in SMC individuals. Exploring the influence of biological variables on AD biomarkers is crucial for their clinical validation in blood.
Published: 2020

9. Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome : a cross-sectional study

Author: Juan Fortea, Sylvain Lehmann, Shahid Zaman, Victor Montal, Tiina Annus, Maria Carmona-Iragui, Sandra Giménez, Jordi Clarimón, Bessy Benejam, Valle Camacho, Teresa Estellés, Susana Fernández, Olivia Belbin, Laura Videla, Anthony J. Holland, Ricardo S. Osorio, Jordi Pegueroles, Alberto Lleó, Isabel Barroeta, Sílvia Valldeneu, Rafael Blesa, Liam R. Wilson, Sofía González-Ortiz, Miren Altuna, Laia Muñoz, Daniel Alcolea, Sebastián Videla, Eduard Vilaplana, Ignacio Illán-Gala, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB), IMIM-Hospital del Mar, Generalitat de Catalunya, University of Cambridge [UK] (CAM), New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), University of Barcelona, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health., Retiveau, Nolwenn, Holland, Anthony [0000-0003-4107-130X], Zaman, Shahid [0000-0003-1639-6014], and Apollo - University of Cambridge Repository
Subjects: Apolipoprotein E, MESH: United Kingdom, positron emission tomography, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, nerve degeneration, Disease, 0302 clinical medicine, middle aged, nuclear magnetic resonance imaging, education.field_of_study, MESH: Middle Aged, adult, General Medicine, Amyloidosis, cohort analysis, MESH: Case-Control Studies, MESH: Amyloid beta-Peptides, MESH: tau Proteins, priority journal, Marcadors bioquímics, Alzheimer disease, medicine.medical_specialty, diagnostic imaging, complication, tau Proteins, Article, cerebrospinal fluid, 03 medical and health sciences, MESH: Cross-Sectional Studies, Apolipoproteins E, Alzheimer Disease, MESH: Spain, cross-sectional study, Humans, neurofilament protein, Cognitive Dysfunction, human, procedures, neurofilament protein L, education, MESH: Prevalence, MESH: Humans, ApoE protein, human, intellectual impairment, Case-control study, MESH: Adult, case control study, medicine.disease, major clinical study, mortality, protein phosphorylation, Cross-Sectional Studies, amyloid beta protein, Case-Control Studies, Positron-Emission Tomography, Down Syndrome, MESH: Alzheimer Disease, Biomarkers, Pediatrics, Down syndrome, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, 030204 cardiovascular system & hematology, MESH: Magnetic Resonance Imaging, MESH: Cognitive Dysfunction, MESH: Fluorodeoxyglucose F18, Neurofilament Proteins, cognitive defect, Prevalence, 030212 general & internal medicine, MESH: Neurofilament Proteins, apolipoprotein E, amyloid beta protein[1-40], Middle Aged, biological marker, MESH: Apolipoproteins E, Magnetic Resonance Imaging, MESH: Positron-Emission Tomography, unclassified drug, fluorodeoxyglucose f 18, neurofilament light chain, female, Biomarker (medicine), medicine.symptom, Cambridge Cognitive Examination for Older Adults with Down Syndrome, Adult, Population, prevalence, Asymptomatic, tau protein, male, blood, Fluorodeoxyglucose F18, medicine, Dementia, controlled study, MESH: Amyloidosis, amyloidosis, Amyloid beta-Peptides, business.industry, amyloid beta protein[1-42], [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Down Syndrome, neurologic disease assessment, Down, Síndrome de, threonine, United Kingdom, Spain, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Alzheimer, MESH: Biomarkers, pathology, business, metabolism
Abstract: Background: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. Methods: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid ß peptides 1–42 and 1–40 and their ratio (Aß1–42/1–40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate. Findings: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aß1–42/1–40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5–54·1), and Alzheimer's disease dementia at 53·7 years (49·5–57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90–100% in the seventh decade of life. Interpretation: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments. Funding: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license
Published: 2020

10. The protofilament architecture of a de novo designed coiled coil-based amyloidogenic peptide

Author: Beate Koksch, Benjamin Bardiaux, Hartmut Oschkinat, Hans von Berlepsch, Anne Diehl, Mônica S. Freitas, Franziska Emmerling, Jork Leiterer, Enrico Brandenburg, Kristin Folmert, Ulla I. M. Gerling-Driessen, Christoph Böttcher, Raheleh Rezaei Araghi, Kevin Pagel, Freie Universität Berlin, Universidade Federal do Rio de Janeiro (UFRJ), Leibniz Forschungsinstitut für Molekulare Pharmakolgie = Leibniz Institute for Molecular Pharmacology [Berlin, Allemagne] (FMP), Leibniz Association, BAM Federal Institute for Materials Research and Testing, Federal Institute for Materials Research and Testing - Bundesanstalt für Materialforschung und -prüfung (BAM), Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Alexander von Humboldt Foundation Georg Forster Research Fellowship and by the CAPES-DAAD Bilateral Exchange of Academics (both awarded to M.S.F.), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Amyloid, Materials science, [SDV]Life Sciences [q-bio], MESH: Protein Structure, Secondary, Amyloidogenic Proteins, Peptide, MESH: Amino Acid Sequence, Microscopy, Atomic Force, 010402 general chemistry, 01 natural sciences, Protein Structure, Secondary, law.invention, 03 medical and health sciences, Protein Domains, Alzheimer Disease, Structural Biology, law, MESH: Nuclear Magnetic Resonance, Biomolecular, Electron microscopy, Humans, Amino Acid Sequence, Nuclear Magnetic Resonance, Biomolecular, Amyloid fibrils, MESH: Microscopy, Atomic Force, chemistry.chemical_classification, Coiled coil, MESH: Amyloid, MESH: Amyloidogenic Proteins, MESH: Humans, MESH: Peptides, Scattering, Cryoelectron Microscopy, Polymer, 0104 chemical sciences, 030104 developmental biology, chemistry, Transmission electron microscopy, Biophysics, MESH: Protein Domains, Substructure, MESH: Cryoelectron Microscopy, Electron microscope, Peptides, MESH: Alzheimer Disease
Abstract: International audience; Amyloid fibrils are polymers formed by proteins under specific conditions and in many cases they are related to pathogenesis, such as Parkinson's and Alzheimer's diseases. Their hallmark is the presence of a β-sheet structure. High resolution structural data on these systems as well as information gathered from multiple complementary analytical techniques is needed, from both a fundamental and a pharmaceutical perspective. Here, a previously reported de novo designed, pH-switchable coiled coil-based peptide that undergoes structural transitions resulting in fibril formation under physiological conditions has been exhaustively characterized by transmission electron microscopy (TEM), cryo-TEM, atomic force microscopy (AFM), wide-angle X-ray scattering (WAXS) and solid-state NMR (ssNMR). Overall, a unique 2-dimensional carpet-like assembly composed of large coexisiting ribbon-like, tubular and funnel-like structures with a clearly resolved protofilament substructure is observed. Whereas electron microscopy and scattering data point somewhat more to a hairpin model of β-fibrils, ssNMR data obtained from samples with selectively labelled peptides are in agreement with both, hairpin structures and linear arrangements.
Published: 2018

11. Detection of amyloid beta peptides in body fluids for the diagnosis of alzheimer's disease: Where do we stand?

Author: Sylvain Lehmann, Christophe Hirtz, Shushil Choubey, Alberto Lleó, Mysore Sridhar Santosh, Constance Delaby, Bhavana Veerabhadrappa, Juan Fortea, Jérôme Vialaret, Daniel Alcolea, Centre For Incubation, Innovation, Research and Consultancy (CIIRC), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hospital de la Santa Creu i Sant Pau, Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), and TRANS INTEGRA HEALTH CARE PRIVATE LIMITED
Subjects: Amyloid beta, Amyloid peptides, Clinical Biochemistry, Tau protein, tau Proteins, Disease, 030204 cardiovascular system & hematology, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, MESH: Body Fluids, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Alzheimer Disease, Diagnosis, Medicine, Humans, MESH: Saliva, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Peptide Fragments, Saliva, Body fluid, MESH: Humans, Amyloid beta-Peptides, biology, medicine.diagnostic_test, business.industry, Lumbar puncture, Biochemistry (medical), [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, MESH: Amyloid beta-Peptides, Peptide Fragments, 3. Good health, MESH: tau Proteins, Body Fluids, Blood, 030220 oncology & carcinogenesis, biology.protein, MESH: Biomarkers, Disease Progression, Biomarker (medicine), MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, business, MESH: Alzheimer Disease, Biomarkers
Abstract: International audience; Alzheimer's disease (AD) is an incurable neurodegenerative disease characterized by progressive decline of cognitive abilities. Amyloid beta peptides (Aβ), Tau proteins and the phosphorylated form of the Tau protein, p-Tau, are the core pathological biomarkers of the disease, and their detection for the diagnosis of patients is progressively being implemented. However, to date, their quantification is mostly performed on cerebrospinal fluid (CSF), the collection of which requires an invasive lumbar puncture. Early diagnosis has been shown to be important for disease-modifying treatment, which is currently in development, to limit the progression of the disease. Nevertheless, the diagnosis is often delayed to the point where the disease has already progressed, and the tools currently available do not allow for a systematic follow-up of patients. Thus, the search for a molecular signature of AD in a body fluid such as blood or saliva that can be collected in a minimally invasive way offers hope. A number of methods have been developed for the quantification of core biomarkers, especially in easily accessible fluids such as the blood, that improve their accuracy, specificity and sensitivity. This review summarizes and compares these approaches, focusing in particular on their use for Aβ detection, the earliest biomarker to be modified in the course of AD. The review also discusses biomarker quantification in CSF, blood and saliva and their clinical applications.
Published: 2019

12. Lipid Biomarkers in Alzheimer's Disease

Author: Gérard Lizard, Mohamed Hammami, Amira Zarrouk, Mohamed El Ayeb, Thibault Moreau, Mustapha Cherkaoui-Malki, Meryam Debbabi, El Mostafa Karym, Boubker Nasser, Asmaa Badreddine, Maryem Bezine, Olivier Rouaud, Laboratoire Bio-PeroxIL. Biochimie du peroxysome, inflammation et métabolisme lipidique [Dijon] (BIO-PEROXIL), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Monastir - University of Monastir (UM), Université de Sousse, Laboratoire des Venins et Biomolécules Thérapeutiques - Laboratory of Venoms and Therapeutic Biomolecules (LR11IPT08), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Mémoire Ressources et Recherche [Dijon] (CMRR Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Université Hassan 1er [Settat], The work on lipid biomarkers carried out by the team ‘Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism’ EA7270 / Univ. Bourgogne Franche-Comté / INSERM is financially supported by: INSERM, Université de Bourgogne, ASSAD (Louhans, France), Department of Neurology (University Hospital, Dijon, France), Memory Center, Resources and Research of Burgundy (CMRR / University Hospital, Dijon, France), and Association pour le Développement des Sciences Neurologiques en Bourgogne (ADSNB, Dijon, France) and Association Bourguignonne pour les Applications des Sciences de l'Information en Médecine (ABASIM, Dijon, France). This work was also supported by grants from: Univ. Monastir (Monastir, Tunisia), Univ. El Manar (Tunis, Tunisia), Pasteur Institut (Tunis, Tunisia), Action Intégrée of the Comité Mixte Inter-Universitaire Franco-Marocain (CMIFM, AIMA/14/310, EGIDE) from the PHC Volubilis/Toubkal program, Ministère des Affaires Etrangères, Conseil Régional de Bourgogne, Ministère de l’enseignement et de la Recherche and Projet Sectoriel CNRST.
Subjects: 0301 basic medicine, medicine.medical_specialty, Lipid Metabolism Disorder, Amyloid, phospholipids, [SDV]Life Sciences [q-bio], Biology, fatty acids, lipids, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Alzheimer Disease, Internal medicine, medicine, Animals, Humans, Dementia, MESH: Animals, MESH: Lipid Metabolism, MESH: Humans, Cholesterol, biomarkers, cholesterol, Lipid metabolism, Peroxisome, Lipid Metabolism, medicine.disease, MESH: Lipids, 3. Good health, 030104 developmental biology, Endocrinology, Neurology, chemistry, Docosahexaenoic acid, Alzheimer, MESH: Biomarkers, oxysterols, lipids (amino acids, peptides, and proteins), Neurology (clinical), Alzheimer's disease, MESH: Alzheimer Disease, 030217 neurology & neurosurgery
Abstract: Background: There are now significant evidences that lipid metabolism is affected in numerous neurodegenerative diseases including Alzheimer’s disease. These dysfunctions lead to abnormal levels of certain lipids in the brain, cerebrospinal fluid and plasma. It is consequently of interest to establish lipid profiles in neurodegenerative diseases. This approach, which can contribute to identify lipid biomarkers of Alzheimers' disease, can also permit to identify new therapeutic targets. It was therefore of interest to focus on central and peripheral biomarkers in Alzheimer's disease. Methods: A review of the literature on 148 papers was conducted. Based on this literature, the involvement of lipids (cholesterol and oxysterols, fatty acids, phospholipids) in Alzheimer's disease has been proposed. Results: Of the 148 references cited for lipid biomarkers for Alzheimer's disease, 65 refer to cholesterol and oxysterols, 35 to fatty acids and 40 to phospholipids. Among these lipids, some of them such as 24S-hydroxyckolesterol, open up new therapeutic perspectives in gene therapy, in particular. The results on the very long-chain fatty acids suggest the potential of peroxisomal dysfunctions in Alzheimer's disease. As for the phospholipids, they could constitute interesting biomarkers for detecting the disease at the prodromal stage. Conclusion: There are now several lines of evidence that lipids play fundamental roles in the pathogenesis of AD and that some of them have a prognostic and diagnosis value. This may pave the way for the identification of new therapeutic targets, new effective drugs and / or new treatments.
Published: 2018

13. Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer’s Disease Before 51 Years

Author: Aline Zarea, Eloi Magnin, Stéphane Epelbaum, Claire Paquet, Valérie Chauviré, Florence Pasquier, Anne Boland, Marie Sarazin, David Wallon, Bruno Salomon, Dominique Campion, Olivier Godefroy, Olivier Martinaud, Mathilde Sauvée, Sophie Auriacombe, Cecilia Marelli, Frédérique Etcharry-Bouyx, Gaël Nicolas, Jean-François Deleuze, Anne-Claire Richard, Vincent de la Sayette, Audrey Gabelle, Thérèse Rivasseau Jonveaux, Stéphane Rousseau, Jérémie Pariente, Mathieu Ceccaldi, Maïté Formaglio, Anne Rovelet-Lecrux, Didier Hannequin, Adeline Rollin-Sillaire, Bernard Croisile, Isabelle Le Ber, Morgane Lacour, Olivier Quenez, Olivier Rouaud, Muriel Quillard-Muraine, Claire Boutoleau-Bretonnière, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), CHU Rouen, Normandie Université (NU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de neurologie [Rouen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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], 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), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-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)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Neurosciences Fonctionnelles et Pathologies (LNFP), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Lyon], CHU Lyon, Hospices Civils de Lyon (HCL), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 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), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), 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)-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)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, MESH: Mutation, 03 medical and health sciences, Amyloid beta-Protein Precursor, 0302 clinical medicine, MESH: Whole Exome Sequencing, Alzheimer Disease, Risk Factors, MESH: Risk Factors, MESH: Amyloid beta-Protein Precursor, PSEN2, Genotype, Genetic variation, Presenilin-2, Exome Sequencing, medicine, PSEN1, Presenilin-1, Humans, Early-onset Alzheimer's disease, Genetic Predisposition to Disease, Risk factor, Allele, Exome sequencing, Genetics, MESH: Humans, MESH: Middle Aged, business.industry, General Neuroscience, MESH: Genetic Predisposition to Disease, General Medicine, Middle Aged, medicine.disease, MESH: Presenilin-1, MESH: Male, 3. Good health, MESH: Presenilin-2, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Female, Geriatrics and Gerontology, business, MESH: Female, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract: International audience; Background:Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer’s disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants.Objective:To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. Methods:We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. Results:Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p
Published: 2019

14. Multi-target-directed ligands for treating Alzheimer's disease: Butyrylcholinesterase inhibitors displaying antioxidant and neuroprotective activities

Author: Janko Kos, Anja Pišlar, Xavier Brazzolotto, Marko Jukič, Stanislav Gobec, Jacques-Philippe Colletier, Nicolas Coquelle, Simon Žakelj, Florian Nachon, Janez Mravljak, Damijan Knez, Matej Sova, Faculty of Pharmacy, University of Ljubljana, Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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), Toxicology, Centre de Recherches du Service de Santé des Armées, Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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 Institut de Recherche Biomédicale des Armées (IRBA)
Subjects: 0301 basic medicine, Models, Molecular, Antioxidant, DPPH, Multi-target-directed ligands, medicine.medical_treatment, MESH: Drug Design, Ligands, Antioxidants, chemistry.chemical_compound, 0302 clinical medicine, 8-hydroxyquinoline, Piperidines, Drug Discovery, MESH: Ligands, Butyrylcholinesterase, chemistry.chemical_classification, MESH: Butyrylcholinesterase, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], General Medicine, MESH: Neuroprotective Agents, Alzheimer's disease, MESH: Amyloid beta-Peptides, 3. Good health, MESH: Piperidines, Neuroprotective Agents, Biochemistry, Efflux, MESH: Caco-2 Cells, MESH: Cholinesterase Inhibitors, Intracellular, MESH: Models, Molecular, MESH: Cell Line, Tumor, Neuroprotection, 03 medical and health sciences, Alzheimer Disease, Cell Line, Tumor, medicine, Humans, Chelation, Pharmacology, Reactive oxygen species, MESH: Humans, Amyloid beta-Peptides, Organic Chemistry, MESH: Antioxidants, 030104 developmental biology, chemistry, Drug Design, Cholinesterase Inhibitors, Caco-2 Cells, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract: International audience; The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay. The crystal structure of compound 11 in complex with butyrylcholinesterase revealed the molecular basis for its low nanomolar inhibition of butyrylcholinesterase (Ki = 1.09 ± 0.12 nM). In addition, compounds 8 and 11 show metal-chelating properties, and reduce the redox activity of chelated Cu2+ ions in a Cu-ascorbate redox system. Compounds 8 and 11 decrease intracellular levels of reactive oxygen species, and are not substrates of the active efflux transport system, as determined in Caco2 cells. Compound 11 also protects neuroblastoma SH-SY5Y cells from toxic Aβ1-42 species. These data indicate that compounds 8 and 11 are promising multifunctional lead ligands for treatment of Alzheimer's disease.
Published: 2018

15. Ecological relevance of the Iowa gambling task in patients with Alzheimer's disease and mild cognitive impairment

Author: Marie-Christine Gély-Nargeot, Sophie Bayard, J.-P. Jacus, Centre Hospitalier du Val d'Ariège, Dynamique des capacités humaines et des conduites de santé (EPSYLON), and Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM)
Subjects: Male, MESH: Decision Making, MESH: Socioeconomic Factors, MESH: Awareness, Decision Making, Disease, Neuropsychological Tests, Personal autonomy, 050105 experimental psychology, MESH: Cognitive Dysfunction, 03 medical and health sciences, 0302 clinical medicine, MESH: Aged, 80 and over, Alzheimer Disease, Rating scale, Humans, Medicine, Cognitive Dysfunction, 0501 psychology and cognitive sciences, Relevance (information retrieval), In patient, Cognitive impairment, MESH: Gambling, Aged, Aged, 80 and over, MESH: Aged, MESH: Humans, Ecology, business.industry, MESH: Personal Autonomy, 05 social sciences, Mild cognitive impairment, MESH: Neuropsychological Tests, Alzheimer's disease, Awareness, Iowa gambling task, MESH: Male, Socioeconomic Factors, Neurology, Gambling, Female, Neurology (clinical), business, MESH: Female, 030217 neurology & neurosurgery, MESH: Alzheimer Disease, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Decision-making
Abstract: Background In spite of their extensive use, the ecological relevance of tasks dedicated to assessing real-world decision-making in a laboratory setting remains unclear. Objectives Our study aimed to evaluate the relationship between decision-making and behavioral competency and awareness of limitations. Methods A total of 20 patients with Alzheimer's disease (AD), 20 with amnestic mild cognitive impairment (aMCI) and 20 healthy controls (HC) were assessed for decision-making using the Iowa Gambling Task (IGT). Behavioral competency was evaluated by the Patient Competency Rating Scale (PCRS), which requires each participant and a relative to answer the same 30 questions on participant's competency and to rate each item, while awareness of limitations was evaluated by subtracting the self-rated score from the relative-rated score. Results Using the median-split approach, the proportion of disadvantageous decision-makers was higher in both the MCI and AD groups than in HC (P = 0.02 and P = 0.03, respectively), with no differences between clinical groups. The percentage of participants with poorer behavioral competency was also higher in the MCI and AD than in the HC (self-rated: P = 0.025 and P = 0.01, respectively; relative-rated: P = 0.008 and P = 0.008, respectively), again with no differences between MCI and AD. All groups were comparable in awareness. For all participants, disadvantageous decision-making was associated with both reduced behavioral competency and poor awareness of limitations (OR: 3.47, P = 0.03 and OR: 5.4, P = 0.004, respectively). Conclusion Our findings support the ecological relevance of the IGT. Behavioral competency integrity and awareness of limitations are both associated with advantageous decision-making profiles.
Published: 2018

16. Co-modulation of an allosteric modulator of nicotinic receptor-cholinesterase inhibitor (galantamine) and a 5-HT4 receptor agonist (RS-67333): effect on scopolamine-induced memory deficit in the mouse

Author: Thomas Freret, Véronique Lelong-Boulouard, Pierre Lecouflet, François Dauphin, Katia Hamidouche, Michel Boulouard, Groupe Mémoire et Plasticité comportementale (GMPc), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), and Université de Caen Normandie - UFR Santé (UNICAEN Santé)
Subjects: Male, 0301 basic medicine, MESH: Serotonin 5-HT4 Receptor Agonists, Nicotinic Antagonists, Receptors, Nicotinic, Pharmacology, Neurodegenerative, MESH: Allosteric Regulation, Mice, 0302 clinical medicine, Piperidines, MESH: Animals, Aniline Compounds, [SDV.BA]Life Sciences [q-bio]/Animal biology, Spontaneous alternation, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Memory Disorders, 3. Good health, Nicotinic agonist, MESH: Piperidines, Acetylcholinesterase inhibitor, MESH: Receptors, Nicotinic, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Cholinesterase Inhibitors, medicine.drug, Agonist, Serotonin, Allosteric modulator, medicine.drug_class, Scopolamine, MESH: Receptors, Serotonin, 5-HT4, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Partial agonist, MESH: Scopolamine, MESH: Aniline Compounds, Serotonin 5-HT4 Receptor Agonists, 03 medical and health sciences, Allosteric Regulation, Alzheimer Disease, Memory, medicine, Galantamine, Animals, MESH: Mice, MESH: Galantamine, Memory Disorders, Behavior, business.industry, MESH: Nicotinic Antagonists, Symptomatic relief, MESH: Male, 030104 developmental biology, Cholinesterase Inhibitors, Receptors, Serotonin, 5-HT4, business, Neuroscience, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract: It is widely assumed that the upcoming therapeutics for Alzheimer’s disease will require to act on more than one target to be effective. We investigated here whether a combination of the nicotinic receptor allosteric modulator/cholinesterase inhibitor galantamine can act synergistically with the type 4 serotonin receptor (5-HT4R) partial agonist, RS-67333, to counterbalance deficits in short- and long-term memory. To select sub-efficacious doses of both drugs, dose-response studies were first performed on the scopolamine-induced deficits of spontaneous alternation in the Y-maze task and of acquisition and retrieval processes in a passive avoidance task. For spontaneous alternation behavior, combination of 1 mg/kg galantamine and 0.5 mg/kg RS-67333 fully reversed the deficit. In the passive avoidance task, no sub-efficacious doses could be found in the retention paradigm, but a beneficial effect of the association has been demonstrated in the acquisition paradigm. Mnesic effects of galantamine can be thus potentiated by activation of 5-HT4R. Such a combination treatment might (1) strengthen symptomatic relief, (2) attenuate adverse effects given the lower doses of each compound required, and (3) afford a disease-modifying effect given the known action of 5-HT4R on amyloidogenesis cascade.
Published: 2017

17. Évaluation de la performance diagnostique de l’imagerie hybride TEP-IRM pour l’exploration des troubles cognitifs dans la pratique clinique

Author: Bourrelier, Stéphanie, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), and Anne Bertrand
Subjects: PET-MR, MESH: Diagnosis, TEP-IRM, MESH: Work Performance, Performance diagnostique, Alzheimer disease, Maladie d’Alzheimer, Diagnostic accuracy, MESH: Positron-Emission Tomography, MESH: Alzheimer Disease, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Magnetic Resonance Imaging
Abstract: Introduction : l'objectif de notre étude était d'évaluer la valeur diagnostique de l'imagerie hybride TEP-IRM pour l'exploration des troubles cognitifs, de déchiffrer la contribution respective de l'imagerie IRM et TEP-FDG dans le diagnostic final et d'identifier le diagnostic ajouté de la volumétrie automatique de l'hippocampe. Méthodes : nous avons analysé rétrospectivement les examens TEP-IRM de 48 patients adressés à nos institutions pour l'exploration de troubles cognitifs et ayant des biomarqueurs dans le LCR réalisés. La TEP-FDG et les séquences morphologiques ont été analysés séparément puis conjointement, en aveugle des symptômes cliniques. Résultats : dans notre étude, La TEP-IRM a diagnostiqué 29 patients MA sur 34 (85.3% des patients) avec des biomarqueurs positifs. Elle a une bonne performance pour classer correctement les patients MA des non MA (Se : 85.3% ; Sp : 78. 6% ; BA : 82 .0%). Sa performance diagnostique et le niveau de confiance étaient plus élevés que celles de la TEP-FDG ou de l’IRM seules. La volumétrie automatique de l'hippocampe n'a pas discriminé les patients MA des patients non MA. Discussion : la TEP-IRM peut être utilisé dans la pratique clinique pour l'exploration de troubles cognitifs, avec une bonne performance diagnostique pour identifier les patients MA des patients non MA. Elle a une meilleure performance diagnostique avec un meilleur niveau de confiance que la TEP-FDG ou l’IRM seules. La volumétrie hippocampique ne permet pas de différencier les patients MA des non MA.
Published: 2017

18. CD36 gene polymorphism is associated with Alzheimer's disease

Author: Vladimir J. Balcar, Alice Hálová, Vladimir Janout, Laura Ewerlingová, Jan Lochman, Jana Janoutová, Naim Akhtar Khan, Omar Šerý, Department of biochemistry, Masaryk University, Masaryk University [Brno] (MUNI), Institute of Animal Physiology and Genetics (Brno), Institute of Animal Physiology and Genetics, Department of Epidemiology and Public Health [university of Ostrava], Lékařská fakulta / Faculty of Medicine [University of Ostrava], Ostravská univerzita / University of Ostrava-Ostravská univerzita / University of Ostrava, Equipe NuTox (LNC - U1231) (NUTOX), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Bosch Institute [Sydney], The University of Sydney, Discipline of Anatomy and Histology {University of Sydney], Masaryk University, Equipe NuTox (LNC - U1231) ( NUTOX ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and The University of Sydney [Sydney]
Subjects: 0301 basic medicine, Apolipoprotein E, MESH : Oxidative Stress, CD36 Antigens, Male, MESH : Polymorphism, Genetic, CD36, MESH : Aged, MESH : Alzheimer Disease, MESH : Genotype, Biochemistry, Gene, MESH: Genotype, 0302 clinical medicine, MESH: Cholesterol, MESH : Female, MESH : Cholesterol, Genetics, MESH: Aged, MESH: Oxidative Stress, biology, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, General Medicine, 3. Good health, MESH : Antigens, CD36, Cholesterol, Interleukin 18, Female, ApoE, Genotype, MESH : Male, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, MMSE, Association, 03 medical and health sciences, Alzheimer Disease, MESH: Polymorphism, Genetic, SNP, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, Polymorphism, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetic association, Aged, Polymorphism, Genetic, MESH: Humans, MESH: Antigens, CD36, MESH : Humans, MESH: Male, Oxidative Stress, 030104 developmental biology, biology.protein, MESH : Genetic Predisposition to Disease, Gene polymorphism, MESH: Female, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract: IF 3.112; International audience; CD36 gene encodes a membrane glycoprotein (type B scavenger receptor) present on the surface of many types of cells and having multiple cellular functions ranging from angiogenesis to gustatory perception of fatty acids. Using a case control genetic association approach we have analyzed selected single nucleotide polymorphisms (SNP's) in a total of 859 patients with Alzheimer's disease (AD) and controls and have identified the allele A in rs3211892 polymorphism of CD36 gene as significantly increasing the risk of AD. Additionally we have investigated, in the same sample of control subjects and patients, SNP's in ApoE gene and confirmed that the previously identified AD-associated SNP's indeed increased the risk and decreased the age of onset of AD as reported by others earlier. Based on the current knowledge of CD36 biochemistry we propose that the AD risk-imparting variants of CD36 alter cholesterol homeostasis, oxidation stress or induce pathological inflammatory cascades. The SNP rs3211892 has previously been associated with heart disease and other conditions but the present study is the first to identify a significant association between variations in CD36 gene and the risk of Alzheimer's disease.
Published: 2017

19. A Precision Medicine Initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling

Author: Stanley Durrleman, Jean-Christophe Corvol, Erfan Younesi, Bruno Dubois, Karl Broich, Simone Lista, Sid E. O'Bryant, Harald Hampel, Valentina Escott-Price, Katrine Rojkova, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), University of North Texas Health Science Center [Fort Worth], Algorithms, models and methods for images and signals of the human brain (ARAMIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), European Society for Translational Medicine (EUSTM), Cardiff University, Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Federal Institute of Drugs and Medical Devices [Bonn], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Inria de Paris, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris
Subjects: 0301 basic medicine, MESH: Health Services Needs and Demand, medicine.medical_specialty, Pathology, Neurology, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, International Cooperation, Alzheimer precision medicine initiative, Disease, MESH: Precision Medicine, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Medicine, Humans, systems medicine, Precision Medicine, Intensive care medicine, Health Services Needs and Demand, MESH: Humans, business.industry, integrative disease modeling, precision medicine initiative, Obstetrics and Gynecology, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], systems biology, General Medicine, Precision medicine, R1, 3. Good health, Clinical trial, Systems medicine, MESH: International Cooperation, 030104 developmental biology, Drug development, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], MESH: Biomarkers, Biomarker (medicine), business, Magic bullet, Alzheimer’s disease, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, 030217 neurology & neurosurgery, MESH: Alzheimer Disease, Biomarkers
Abstract: International audience; After intense scientific exploration and more than a decade of failed trials, Alzheimer's disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up. The Alzheimer's Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials.
Published: 2017

20. MRI, FDG-TEP and Florbetapir-TEP in AD

Author: Ahmed Abbas, Florence Mézenge, Francis Eustache, Audrey Perrotin, Brigitte Landeau, Gaël Chételat, Renaud La Joie, Vincent de La Sayette, Caroline Hommet, Béatrice Desgranges, M Ibazizène, Denis Guilloteau, L. Barre, Vincent Camus, Neuropsychologie cognitive et neuroanatomie fonctionnelles de la mémoire humaine, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Développements Méthodologiques en Tomographie par Emission de Positons (LDM-TEP), 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)-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Centre Mémoire Ressources Recherche (CMRR), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Psychiatrique Universitaire, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Laboratoire de Médecine Nucléaire, Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), This study was funded by Agence Nationale de la Recherche (ANR LONGVIE 2007), Programme Hospitalier de Recherche Clinique (PHRC National 2008), Région Basse Normandie, and Institut National de la Santé et de la Recherche Médicale (Inserm), including the Inserm Liliane Bettencourt School (MD-PhD Program)., Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), 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-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: Male, Pathology, MESH: Hippocampus, Hippocampus, Disease, Neuropsychological Tests, MESH: Magnetic Resonance Imaging, 0302 clinical medicine, β amyloid, Cortex (anatomy), Image Processing, Computer-Assisted, MESH: Neuroimaging, MESH: Brain Chemistry, MESH: Aged, 0303 health sciences, medicine.diagnostic_test, General Neuroscience, MESH: Neuropsychological Tests, Neurofibrillary Tangles, Articles, MESH: Image Processing, Computer-Assisted, Magnetic Resonance Imaging, MESH: Positron-Emission Tomography, MESH: Amyloid beta-Peptides, medicine.anatomical_structure, Positron emission tomography, Educational Status, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Psychology, medicine.medical_specialty, Neuroimaging, MESH: Atrophy, 03 medical and health sciences, Atrophy, Alzheimer Disease, medicine, Humans, Dementia, Pathological, Aged, 030304 developmental biology, Brain Chemistry, MESH: Humans, Amyloid beta-Peptides, MESH: Biological Markers, medicine.disease, MESH: Male, Positron-Emission Tomography, MESH: Educational Status, MESH: Female, MESH: Alzheimer Disease, Biomarkers, 030217 neurology & neurosurgery, MESH: Neurofibrillary Tangles
Abstract: Gray matter atrophy, glucose hypometabolism, and β-amyloid Aβ deposition are well-described hallmarks of Alzheimer's disease, but their relationships are poorly understood. The present study aims to compare the local levels of these three alterations in humans with Alzheimer's disease. Structural magnetic resonance imaging,18F-fluorodeoxyglucose positron emission tomography (PET), and18F-florbetapir PET data from 34 amyloid-negative healthy controls and 20 demented patients with a high probability of Alzheimer's disease etiology (attested using neuroimaging biomarkers as recently recommended) were analyzed. For each patient and imaging modality, age-adjustedZ-score maps were computed, and direct between-modality voxelwise comparison and correlation analyses were performed. Significant differences in the levels of atrophy, hypometabolism, and Aβ deposition were found in most brain areas, but the hierarchy differed across regions. A cluster analysis revealed distinct subsets of regions: (1) in the hippocampus, atrophy exceeded hypometabolism, whereas Aβ load was minimal; (2) in posterior association areas, Aβ deposition was predominant, together with high hypometabolism and lower but still significant atrophy; and (3) in frontal regions, Aβ deposition was maximal, whereas structural and metabolic alterations were low. Atrophy and hypometabolism significantly correlated in the hippocampus and temporo-parietal cortex, whereas Aβ load was not significantly related to either atrophy or hypometabolism. These findings provide direct evidence for regional variations in the hierarchy and relationships between Aβ load, hypometabolism, and atrophy. Altogether, these variations probably reflect the differential involvement of region-specific pathological or protective mechanisms, such as the presence of neurofibrillary tangles, disconnection, as well as compensation processes.
Published: 2012

21. Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging

Author: Bruno Dubois, Julien Lagarde, Mickael Labit, Guillaume Dorothée, Leonardo Cruz de Souza, Michel Bottlaender, Philippe Gervais, Hélène Corne, Olivier Colliot, Robert A. Comley, Luce Dauphinot, Maxime Bertoux, Lorraine Hamelin, Marie Sarazin, Marie-Claude Potier, Claire Leroy, Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CATI Multicenter Neuroimaging Platform (CATI), F. Hoffmann-La Roche [Basel], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Neurobiologie, Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Service de Neuroradiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Laboratoire de Recherche BioMédicale (LBIOM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de Neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Psychiatrie et Neurosciences (U894), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Système immunitaire et neuroinflammation [CRSA], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Imagerie Moléculaire In Vivo ( IMIV - U1023 ), Service Hospitalier Frédéric Joliot ( SHFJ ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-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 ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CATI Multicenter Neuroimaging Platform ( CATI ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] ( IM2A ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), ESPCI ParisTech-Centre National de la Recherche Scientifique ( CNRS ), Algorithms, models and methods for images and signals of the human brain ( ARAMIS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ) -Inria de Paris, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Laboratoire de Recherche BioMédicale ( LBIOM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, 0301 basic medicine, Fluorine Radioisotopes, Pathology, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH : Aged, MESH : Prospective Studies, MESH : Pyrimidines, MESH : Alzheimer Disease, MESH : Pyrazoles, [ SPI.SIGNAL ] Engineering Sciences [physics]/Signal and Image processing, [ INFO.INFO-CV ] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, MESH: Aged, 80 and over, [ INFO.INFO-TI ] Computer Science [cs]/Image Processing, MESH : Female, Longitudinal Studies, Prospective Studies, MESH: Longitudinal Studies, MESH: Cohort Studies, [ SDV.IB.IMA ] Life Sciences [q-bio]/Bioengineering/Imaging, Aged, 80 and over, MESH : Longitudinal Studies, MESH: Aged, MESH: Middle Aged, [ INFO.INFO-IM ] Computer Science [cs]/Medical Imaging, biology, Amyloidosis, Brain, MESH : Fluorine Radioisotopes, MESH: Follow-Up Studies, Middle Aged, MESH: Positron-Emission Tomography, MESH: Microglia, medicine.anatomical_structure, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Female, Microglia, Alzheimer's disease, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, medicine.medical_specialty, Amyloid, MESH : Male, MESH : Cohort Studies, Grey matter, MESH : Microglia, 03 medical and health sciences, MESH: Brain, Atrophy, Alzheimer Disease, medicine, Translocator protein, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Dementia, MESH : Middle Aged, MESH : Aged, 80 and over, Aged, MESH: Fluorine Radioisotopes, MESH: Humans, business.industry, MESH : Humans, MESH : Positron-Emission Tomography, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], MESH : Follow-Up Studies, medicine.disease, MESH: Male, MESH: Prospective Studies, Pyrimidines, 030104 developmental biology, MESH : Brain, chemistry, Positron-Emission Tomography, MESH: Pyrimidines, biology.protein, Pyrazoles, Neurology (clinical), Pittsburgh compound B, business, MESH: Female, 030217 neurology & neurosurgery, MESH: Pyrazoles, MESH: Alzheimer Disease, Follow-Up Studies
Abstract: International audience; While emerging evidence suggests that neuroinflammation plays a crucial role in Alzheimer's disease, the impact of the microglia response in Alzheimer's disease remains a matter of debate. We aimed to study microglial activation in early Alzheimer's disease and its impact on clinical progression using a second-generation 18-kDa translocator protein positron emission tomography radiotracer together with amyloid imaging using Pittsburgh compound B positron emission tomography. We enrolled 96 subjects, 64 patients with Alzheimer's disease and 32 controls, from the IMABio3 study, who had both (11)C-Pittsburgh compound B and (18)F-DPA-714 positron emission tomography imaging. Patients with Alzheimer's disease were classified as prodromal Alzheimer's disease (n = 38) and Alzheimer's disease dementia (n = 26). Translocator protein-binding was measured using a simple ratio method with cerebellar grey matter as reference tissue, taking into account regional atrophy. Images were analysed at the regional (volume of interest) and at the voxel level. Translocator protein genotyping allowed the classification of all subjects in high, mixed and low affinity binders. Thirty high+mixed affinity binders patients with Alzheimer's disease were dichotomized into slow decliners (n = 10) or fast decliners (n = 20) after 2 years of follow-up. All patients with Alzheimer's disease had an amyloid positive Pittsburgh compound B positron emission tomography. Among controls, eight had positive amyloid scans (n = 6 high+mixed affinity binders), defined as amyloidosis controls, and were analysed separately. By both volumes of interest and voxel-wise comparison, 18-kDa translocator protein-binding was higher in high affinity binders, mixed affinity binders and high+mixed affinity binders Alzheimer's disease groups compared to controls, especially at the prodromal stage, involving the temporo-parietal cortex. Translocator protein-binding was positively correlated with Mini-Mental State Examination scores and grey matter volume, as well as with Pittsburgh compound B binding. Amyloidosis controls displayed higher translocator protein-binding than controls, especially in the frontal cortex. We found higher translocator protein-binding in slow decliners than fast decliners, with no difference in Pittsburgh compound B binding. Microglial activation appears at the prodromal and possibly at the preclinical stage of Alzheimer's disease, and seems to play a protective role in the clinical progression of the disease at these early stages. The extent of microglial activation appears to differ between patients, and could explain the overlap in translocator protein binding values between patients with Alzheimer's disease and amyloidosis controls.
Published: 2016

22. Neurotherapeutic applications of nanoparticles in Alzheimer's disease

Author: Charles Ramassamy, Lé Dao, Sihem Doggui, Jasjeet K Sahni, Javed Ali, Sanjula Baboota, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Department of Pharmaceutics, Faculty of Pharmacy-Jamia Hamdard, Faculté de Médecine, Université Laval [Québec] (ULaval), and The financial support from NSERC (LD) and FQRNT (LD, CR) is gratefully acknowledged.
Subjects: Pathology, Pharmaceutical Science, Disease, MESH: Chelating Agents, Bioinformatics, MESH: Blood-Brain Barrier, Drug Delivery Systems, MESH: Phenols, MESH: Hormones, Degenerative disease, MESH: Animals, Chelating Agents, media_common, education.field_of_study, MESH: Vasoactive Intestinal Peptide, Blood-Brain Barrier, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Drug delivery, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, MESH: Cholinesterase Inhibitors, Vasoactive Intestinal Peptide, Drug, Amyloid, medicine.medical_specialty, media_common.quotation_subject, MESH: Drug Delivery Systems, Population, Phenols, Alzheimer Disease, medicine, Animals, Humans, education, Flavonoids, MESH: Amyloid, MESH: Humans, business.industry, Polyphenols, medicine.disease, Hormones, Targeted drug delivery, Nanoparticles, Cholinesterase Inhibitors, Nanocarriers, business, MESH: Flavonoids, MESH: Alzheimer Disease, MESH: Nanoparticles, MESH: Polyphenols
Abstract: International audience; A rapid increase in incidence of neurodegenerative disorders has been observed with the aging of the population. Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly. It is characterized by memory dysfunction, loss of lexical access, spatial and temporal disorientation and impairment of judgement clinically. Unfortunately, clinical development of drugs for the symptomatic and disease-modifying treatment of AD has resulted in both promise and disappointment. Indeed, a large number of drugs with differing targets and mechanisms of action were investigated with only a few of them being clinically available. The targeted drug delivery to the central nervous system (CNS), for the diagnosis and treatment of neurodegenerative disorders such as AD, is restricted due to the limitations posed by the blood-brain barrier (BBB) as well as due to opsonization by plasma proteins in the systemic circulation and peripheral side-effects. Over the last decade, nanoparticle-mediated drug delivery represents one promising strategy to successfully increase the CNS penetration of several therapeutic moieties. Different nanocarriers are being investigated to treat and diagnose AD by delivering at a constant rate a host of therapeutics over times extending up to days, weeks or even months. This review provides a concise incursion on the current pharmacotherapies for AD besides reviewing and discussing the literature on the different drug molecules that have been successfully encapsulated in nanoparticles (NPs). Some of them have been shown to cross the BBB and have been tested either for diagnosis or treatment of AD. Finally, the route of NPs administration and the future prospects will be discussed.
Published: 2011

23. EHT0202 in Alzheimers Disease: A 3-Month, Randomized, Placebo- Controlled, Double-Blind Study

Author: Vellas, Bruno, Sol, O., Snyder, P.- J., Ousset, P.-J., Haddad, R., Maurin, M., Lemarié, J.-C., Désiré, L., Pando, M.- P., Belliard, S., Blin, J., Terran, F., Pancrazi, M.-P., Boge, T., Bouillat, J., Boutoleau-Bretonnière, Claire, Vercelletto, M., Dantoine, Thierry, Laubarie-Mouret, C., Picat, M.-A., Saulnier, I., Deramecourt, V., Pasquier, F., Hanon, O., Hugonot-Diener, L., Latour, F., Rigaud, A.-S., Lala, F., Sastre-Hengan, N., Belmin, J., Pariel, S., Salom, M., Clair, A., Barres, S., Chartier, J.-P., Delabrousse-Mayoux, P., Dunac, A., Garrigues, G., Gras, P., Gugenheim, M., Neuschwander, P., Pouyet, A., Prince, P.-J., Quiquempois, J.-M., Schmidt, N., Tréfouret, S., Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Gérontopôle, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], EHT0202/002 study group, ExonHit Therapeutics SA, Service de Médecine Gériatrique [CHU Limoges], and CHU Limoges
Subjects: Male, medicine.medical_specialty, Time Factors, Phosphodiesterase Inhibitors, medicine.drug_class, Pilot Projects, Etazolate, Placebo, MESH: Phosphodiesterase Inhibitors, law.invention, Efficacy, Double-Blind Method, Randomized controlled trial, Alzheimer Disease, law, Internal medicine, Humans, Medicine, MESH: Double-Blind Method, Adverse effect, Aged, MESH: Aged, MESH: Humans, business.industry, MESH: Time Factors, MESH: Etazolate, MESH: Pilot Projects, MESH: Male, Clinical trial, Neurology, Tolerability, Acetylcholinesterase inhibitor, Cohort, Physical therapy, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), business, MESH: Female, MESH: Alzheimer Disease
Abstract: International audience; BACKGROUND: EHT0202 (etazolate hydrochloride) is a new compound exhibiting both potential disease-modifying and symptomatic treatment properties in Alzheimer's Disease increasing alpha-secretase activity and sAPP alpha secretion, as well as acting as a GABA-A receptor modulator and as a PDE-4 inhibitor. METHODS: This pilot, randomized, double-blind, placebo-controlled, parallel group, multicentre, Phase IIA study was conducted in 159 randomized patients suffering from mild to moderate Alzheimer's Disease. EHT0202 (40 or 80 mg bid) or placebo was administered as adjunctive therapy to one acetylcholinesterase inhibitor over a 3-month period. This study was designed to assess the clinical safety and tolerability of EHT0202 as a primary objective, with secondary endpoints (cognitive function, daily living activities, behaviour, caregiver burden and global functioning) included to explore clinical efficacy of EHT0202 versus placebo. RESULTS: EHT0202 was shown to be safe and generally well tolerated. Dose-dependent numbers of early withdrawal and central nervous system related adverse events were observed. As expected, since the study was not powered and not designed to show drug efficacy, and except for ratings on the ADCS-ADL scale, no significant differences were seen between treatment groups. CONCLUSIONS: These first encouraging safety results do support further development of EHT0202 in order to assess its clinical efficacy and to confirm its tolerability in a larger cohort of Alzheimer patients and for a longer period.
Published: 2011

24. Molecular Regulations Induced by Acrolein in Neuroblastoma SK-N-SH Cells: Relevance to Alzheimer's Disease

Author: Madeleine Arseneault, Thanh Nam Dang, Georg Waeg, Neven Zarkovic, Charles Ramassamy, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Laboratory for Oxidative Stress, Rudjer Boskovic Institute [Zagreb], Institute of Molecular Biosciences, Karl-Franzens-Universität [Graz, Autriche], Department of Medical Biology, Faculty of Medicine, and Université Laval [Québec] (ULaval)
Subjects: MESH: Cell Line, Tumor, Free Radicals, Protein Carbonylation, DNA Fragmentation, Pharmacology, medicine.disease_cause, MESH: Lipid Peroxidation, Lipid peroxidation, DNA Adducts, Neuroblastoma, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, MESH: Free Radicals, Alzheimer Disease, Cell Line, Tumor, medicine, MESH: DNA Fragmentation, Humans, Acrolein, acrolein, lipid peroxidation, neuroblastoma, Alzheimers disease, 030304 developmental biology, Temporal cortex, chemistry.chemical_classification, 0303 health sciences, Reactive oxygen species, MESH: Humans, MESH: Oxidative Stress, General Neuroscience, General Medicine, Glutathione, MESH: Neuroblastoma, 3. Good health, Oxidative Stress, Psychiatry and Mental health, Clinical Psychology, chemistry, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Immunology, Toxicity, Acrolein, Alzheimer disease, lipid peroxidation, oxidative stress, MESH: Acrolein, Lipid Peroxidation, Geriatrics and Gerontology, MESH: Alzheimer Disease, MESH: DNA Adducts, 030217 neurology & neurosurgery, Oxidative stress
Abstract: International audience; Acrolein is the most reactive aldehyde among the by-products of lipid peroxidation. Growing evidence indicates that acrolein may play an important role in the pathogenesis of Alzheimer's disease (AD). In AD, levels of acrolein are significantly higher in hippocampus and temporal cortex regions of the brain. However, little is known about its toxicity in neuronal cells. Using the neuroblastoma cell line SK-N-SH, our results show that acrolein is toxic from 10 μM, but its toxicity does not induce the activation of caspase-3 and DNA fragmentation. Protein carbonylation and 4-hydroxynonenal levels were increased after 0.5 hr and 1 hr of treatment, respectively. Furthermore acrolein induced a biphasic effect on glutathione levels with a rapid depletion followed by a progressive increase. We have further investigated the regulation of different redox signaling pathways. A treatment with 10 μM of acrolein for 30 min activated NFκB while this activation was suppressed after a 24 hrs of treatment. In contrast, Nrf2 was activated only after 24 hrs of acrolein exposure. Consequently, the expression of heme oxygenase-1 and γ-glutamyl-cysteine-synthase were elevated after 24 hrs of acrolein treatment. Sirt-1 was also upregulated after 24 hrs of acrolein treatment. The p66Shc and ERK1/2 proteins are known to be involved in oxidative stress. Acrolein, at 10 μM, induced the phosphorylation of p66Shc and ERK1/2 only after a short period of treatment. Collectively, these data strengthen the contribution of acrolein in the induction of oxidative stress as observed in mild cognitive impairment and in AD brain.
Published: 2010

25. Longitudinal brain metabolic changes from amnestic mild cognitive impairment to Alzheimer's disease

Author: Marine Fouquet, Fausto Viader, Francis Eustache, Brigitte Landeau, Florence Mézenge, Gaël Chételat, Jean-Claude Baron, V. de la Sayette, Edouard Duchesnay, B. Desgranges, Neuropsychologie cognitive et neuroanatomie fonctionnelles de la mémoire humaine, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuroimagerie Assistée par Ordinateur (LNAO), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Recherches sur la Cognition et l'Apprentissage (CeRCA), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Université de Poitiers, Eustache, Francis, and Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE)
Subjects: Male, Cingulate cortex, Precuneus, Disease, Neuropsychological Tests, Audiology, Brain mapping, MESH: Magnetic Resonance Imaging, MESH: Aged, 80 and over, 0302 clinical medicine, MESH: Fluorodeoxyglucose F18, Cognitive decline, Cognitive impairment, 10. No inequality, Prefrontal cortex, MESH: Brain Mapping, Aged, 80 and over, MESH: Aged, Brain Mapping, 0303 health sciences, MESH: Middle Aged, longitudinal study, Brain, MESH: Neuropsychological Tests, MESH: Follow-Up Studies, Middle Aged, Magnetic Resonance Imaging, MESH: Positron-Emission Tomography, medicine.anatomical_structure, Neurology, Disease Progression, Cardiology, Female, MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, MESH: Amnesia, Psychology, medicine.medical_specialty, Cognitive Neuroscience, Uncinate fasciculus, Article, MESH: Brain, 03 medical and health sciences, Alzheimer Disease, Fluorodeoxyglucose F18, Internal medicine, Image Interpretation, Computer-Assisted, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Aged, 030304 developmental biology, MESH: Humans, business.industry, amnestic Mild Cognitive Impairment, medicine.disease, MESH: Male, MESH: Cognition Disorders, 18FDG-PET monitoring, Positron-Emission Tomography, Posterior cingulate, Amnesia, Neurology (clinical), Cognition Disorders, ventro-medial prefrontal cortex, business, MESH: Image Interpretation, Computer-Assisted, MESH: Female, Neuroscience, MESH: Alzheimer Disease, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: International audience; A sensitive marker for monitoring progression of early Alzheimer's disease would help to develop and test new therapeutic strategies. The present study is aimed at investigating brain metabolism changes over time, as a potential monitoring marker, in patients with amnestic mild cognitive impairment, according to their clinical outcome (converters or non-converters), and in relation to their cognitive decline. Seventeen amnestic mild cognitive impairment patients underwent magnetic resonance imaging and 18FDG-positron emission tomography scans both at inclusion and 18 months later. Baseline and follow-up positron emission tomography data were corrected for partial volume effects and spatially normalized using magnetic resonance imaging data, scaled to the vermis and compared using SPM2. 'PET-PAC' maps reflecting metabolic per cent annual changes were created for correlation analyses with cognitive decline. In the whole sample, the greatest metabolic decrease concerned the posterior cingulate-precuneus area. Converters had significantly greater metabolic decrease than non-converters in two ventro-medial prefrontal areas, the subgenual (BA25) and anterior cingulate (BA24/32). PET-PAC in BA25 and BA24/32 combined allowed complete between-group discrimination. BA25 PET-PAC significantly correlated with both cognitive decline and PET-PAC in the hippocampal region and temporal pole, while BA24/32 PET-PAC correlated with posterior cingulate PET-PAC. Finally, the metabolic change in BA8/9/10 was inversely related to that in BA25 and showed relative increase with cognitive decline, suggesting that compensatory processes may occur in this dorso-medial prefrontal region. The observed ventro-medial prefrontal disruption is likely to reflect disconnection from the hippocampus, both indirectly through the cingulum bundle and posterior cingulate cortex for BA24/32, and directly through the uncinate fasciculus for BA25. Altogether, our findings emphasize the potential of 18FDG-positron emission tomography for monitoring early Alzheimer's disease progression.
Published: 2009

26. Commentary on 'A roadmap for the prevention of dementia II. Leon Thal Symposium 2008.' The Multidomain Alzheimer Preventive Trial (MAPT): A new approach to the prevention of Alzheimer's disease

Author: Gillette-Guyonnet, Sophie, Andrieu, Sandrine, Dantoine, Thierry, Dartigues, Jean-François, Touchon, Jacques, Vellas, Bruno, Mapt Study, Group, Gérontopôle, CHU Toulouse [Toulouse]-Epidémiologie et Analyses en Santé Publique : risques, maladies chroniques et handicap (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie et Analyses en Santé Publique : risques, maladies chroniques et handicap (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Service d'épidémiologie [Toulouse], CHU Toulouse [Toulouse], Service de Médecine Gériatrique [CHU Limoges], CHU Limoges, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologies du système nerveux : recherche épidémiologique et clinique, and Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Gerontology, Research design, Activities of daily living, Epidemiology, Psychological intervention, Disease, Prevention of dementia, law.invention, MESH: Brain, Cellular and Molecular Neuroscience, MESH: Fatty Acids, Omega-3, Developmental Neuroscience, Randomized controlled trial, law, MESH: Exercise Therapy, Medicine, MESH: Data Collection, MESH: Patient Selection, Cognitive decline, MESH: Outcome Assessment (Health Care), MESH: Sample Size, MESH: Humans, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Health Policy, MESH: Research Design, MESH: Biological Markers, MESH: Neuropsychological Tests, Cognitive training, MESH: Cognitive Therapy, MESH: Cognition Disorders, Psychiatry and Mental health, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Disease Progression, Neurology (clinical), Geriatrics and Gerontology, business, MESH: Alzheimer Disease
Abstract: International audience; BACKGROUND: Because no effective curative approaches are available, preventive approaches in the field of Alzheimer's disease (AD) are needed. We present the design of the ongoing Multidomain Alzheimer Preventive Trial (MAPT) Study. Several previous studies suggested that many factors may be involved in the occurrence of AD at late ages. Because of the probable multifactorial nature of AD, it seems logical to initiate multidomain interventions to examine their potential synergistic effects. The MAPT Study aims to evaluate the efficacy of a multidomain intervention (nutritional, physical, and cognitive training) and omega 3 treatment in the prevention of cognitive decline in frail elderly persons aged 70 years or over. The study also collects imaging and biological data that could be used in future AD prevention and treatment trials. METHODS: The MAPT Study is a 3-year, randomized, controlled trial conducted by university hospital practitioners specializing in memory disorders in four French cities (Bordeaux, Limoges, Montpellier, and Toulouse). The study plans to enroll 1200 frail elderly subjects on the basis of at least one of the following criteria: subjective memory complaint spontaneously expressed to a general practitioner, limitation in one instrumental activity of daily living (IADL), and slow walking speed. To demonstrate the protective effect of interventions, subjects are randomized into one of the following four groups: omega 3 alone, multidomain intervention alone, omega 3 plus multidomain intervention, or placebo (n = 300 each). The principal outcome measure is a change in cognitive function at 3 years, as determined by the Grober and Buschke Test. CONCLUSIONS: The MAPT Study is the first preventive trial involving multidomain interventions. Final results should be available in 2013.
Published: 2009

27. Fluorescent BODIPY-Based Zn(II) Complex as a Molecular Probe for Selective Detection of Neurofibrillary Tangles in the Brains of Alzheimer's Disease Patients

Author: Akio Ojida, Guy Lippens, Takashi Sakamoto, Itaru Hamachi, Masa Aki Inoue, Sho Hei Fujishima, Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology (TUMSAT), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Boron Compounds, MESH: Hippocampus, Tau protein, MESH: Boron Compounds, Molecular Probe Techniques, tau Proteins, 010402 general chemistry, Hippocampus, 01 natural sciences, Biochemistry, MESH: Zinc, Catalysis, chemistry.chemical_compound, MESH: Brain, Colloid and Surface Chemistry, Alzheimer Disease, mental disorders, Humans, Phosphorylation, Binding site, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Humans, biology, MESH: Phosphorylation, 010405 organic chemistry, Brain, Neurofibrillary Tangles, General Chemistry, Fluorescence, Phosphorylated Peptide, 0104 chemical sciences, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: tau Proteins, Dissociation constant, MESH: Molecular Probe Techniques, Zinc, Dipicolylamine, chemistry, biology.protein, BODIPY, Molecular probe, MESH: Alzheimer Disease, MESH: Neurofibrillary Tangles
Abstract: International audience; We have developed a new fluorescent binuclear Zn(II) complex for the detection of neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, a representative hallmark of Alzheimer's disease (AD). The probe 1 incorporates a fluorescent BODIPY unit and two Zn(II)-2,2'-dipicolylamine (Dpa) complexes as a binding site for phosphorylated amino acid residues. Using fluorescence titration to evaluate the binding and sensing properties of 1 toward several phosphorylated peptide segments derived from hyperphosphorylated tau protein, we found that 1 binds preferentially to peptides presenting phosphorylated groups at the i and i+4 positions with dissociation constants (K(d)) in the micromolar range. Fluorescence titration with an artificially prepared aggregate of the phosphorylated tau protein (p-Tau) revealed that 1 binds strongly to p-Tau (EC(50) = 9 nM). In contrast, the interactions of 1 were weaker toward artificially prepared aggregates of the nonphosphorylated tau protein (n-Tau; EC(50) = 80 nM) and Abeta(1-42) fibrils (EC(50) = 650 nM). Histological imaging of a hippocampus tissue section obtained from an AD patient revealed that 1 fluorescently visualizes deposits of NFTs and clearly discriminates between NFTs and the amyloid plaques assembled from amyloid-beta peptides, confirming our strategy toward the rational design of a molecular probe for the selective fluorescence detection of NFTs in brain tissue sections.
Published: 2009

28. Infectious Fold and Amyloid Propagation inPodospora anserina

Author: Marie-Lise Maddelein, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Protein Folding, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, animal diseases, 01 natural sciences, Biochemistry, Podospora anserina, Prion Diseases, law.invention, MESH: Recombinant Proteins, law, Genetics, 0303 health sciences, Podospora, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Ure2, Mini-Review, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Saccharomyces cerevisiae, Recombinant Proteins, 3. Good health, Cell biology, Infectious Diseases, Recombinant DNA, MESH: Fungal Proteins, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Protein folding, Amyloid, animal structures, MESH: Protein Folding, Saccharomyces cerevisiae, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Models, Biological, Fungal Proteins, 03 medical and health sciences, Cellular and Molecular Neuroscience, Alzheimer Disease, MESH: Podospora, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, MESH: Amyloid, MESH: Humans, 010405 organic chemistry, MESH: Models, Biological, MESH: Prion Diseases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, biology.organism_classification, nervous system diseases, 0104 chemical sciences, Fungal prion, MESH: Alzheimer Disease
Abstract: International audience; Amyloid protein aggregation is involved in serious neurodegenerative disorders such as Alzheimer's disease and transmissible encephalopathies. The concept of an infectious protein (prion) being the scrapie agent was successfully validated for several yeast and fungi proteins. Ure2, Sup35 and Rnq1 in Saccharomyces cerevisiae and HET-s in Podospora anserina have been genetically and biochemically identified as prion proteins. Studies on these proteins have revealed critical information on the mechanisms of prions appearance and propagation. The prion phenotype correlates with the aggregation state of these particular proteins. In vitro, the recombinant prion proteins form amyloid fibers characterized by rich beta sheet content. In a previous work on the HET-s prion protein Podospora, we demonstrated the infectivity of HET-s recombinant amyloid aggregates. More recently, the structural analysis of the HET-s prion domain associated with in vivo mutagenesis allowed us to propose a model for the infectious fold of the HET-s prion domain. Further investigations to complete this model are discussed in this review, as are relevant questions about the [Het-s] system of Podospora anserina.
Published: 2007

29. Central and Peripheral Agraphia in Alzheimer's Disease: From the Case of Auguste D. to a Cognitive Neuropsychology Approach

Author: Florence Nore, Francis Eustache, Bénédicte Giffard, Vincent de la Sayette, Florence Pasquier, J Lambert, Laboratoire de Neuropsychologie, Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -École pratique des hautes études ( EPHE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Troubles cognitifs vasculaires et dégénératifs, Université de Lille, Sciences et Technologies, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Eustache, Francis
Subjects: Male, Writing, MESH : Aged, MESH : Agraphia, MESH : Alzheimer Disease, Disease, MESH: Language Disorders, Vocabulary, MESH : Vocabulary, MESH: Aged, 80 and over, 0302 clinical medicine, spelling, Reference Values, MESH : Female, Motor skill, MESH: Aged, Aged, 80 and over, MESH: Writing, MESH: Middle Aged, 05 social sciences, MESH: Reference Values, Cognition, Alzheimer's disease, Middle Aged, MESH: Case-Control Studies, MESH : Language Disorders, Spelling, Neuropsychology and Physiological Psychology, Motor Skills, MESH : Motor Skills, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, medicine.symptom, Psychology, Cognitive psychology, MESH : Case-Control Studies, MESH : Male, Cognitive Neuroscience, education, Experimental and Cognitive Psychology, MESH : Reference Values, 050105 experimental psychology, 03 medical and health sciences, Alzheimer Disease, medicine, Humans, Dementia, MESH : Middle Aged, 0501 psychology and cognitive sciences, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Vocabulary, MESH : Aged, 80 and over, Agraphia, Cognitive neuropsychology, Aged, Language Disorders, MESH: Humans, MESH : Humans, medicine.disease, MESH: Male, MESH : Writing, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Case-Control Studies, MESH: Agraphia, MESH: Female, MESH: Alzheimer Disease, 030217 neurology & neurosurgery, MESH: Motor Skills
Abstract: International audience; Since the observation of Auguste D. by Alöis Alzheimer, it is an acknowledged fact that writing is one of the cognitive functions that are weakened early in Alzheimer's disease (AD). This study aimed to examine the cognitive nature of this disorder and question the hypothesis of a standard progression (Platel et al., 1993) from lexical to other central and more peripheral processes. A large group of mild to moderate AD patients (n=59) and a group of healthy elderly controls were submitted to an extensive assessment of both the central and peripheral components of writing. A comparison of groups indicated that AD patients performed more poorly than controls on a wide range of writing measures. It revealed a predominantly lexical disorder, but also found evidence of associated disorders located at different stages in the spelling system (phonological route, graphemic buffer, allographic store, graphic motor patterns). A multiple single-case analysis, using a specific methodology, allowed us to delimit individual profiles of agraphia. It revealed a wide variety of agraphia syndromes, including a far from negligible number of patients with selective damage to one of the central or peripheral components, as well as patients with multiple writing impairments. A positive correlation was observed between the severity of the dementia and spelling/writing measures (lexical and allographic). This study does not support the hypothesis of a uniform progression. Rather, it points to heterogeneous profiles of agraphia and suggests that the first signs of writing impairment in AD stem from changes at different points in the broad anatomical network subserving spelling and writing abilities.
Published: 2007

30. The multiple roles of the α7 nicotinic acetylcholine receptor in modulating glutamatergic systems in the normal and diseased nervous system

Author: Fani Koukouli, Uwe Maskos, Neurobiologie intégrative des Systèmes cholinergiques (NISC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Fani Koukouli is a scholar of the Pasteur Paris University Doctoral Program (PPU) and received a stipend from the Stavros Niarchos Foundation., and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Nervous system, Nicotine, alpha7 Nicotinic Acetylcholine Receptor, [SDV]Life Sciences [q-bio], Neurotransmission, Pharmacology, Biology, Biochemistry, Synaptic plasticity, MESH: alpha7 Nicotinic Acetylcholine Receptor, 03 medical and health sciences, Glutamatergic, chemistry.chemical_compound, [SCCO]Cognitive science, 0302 clinical medicine, Alzheimer Disease, Central Nervous System Diseases, medicine, Humans, Neurotransmitter, 030304 developmental biology, Acetylcholine receptor, 0303 health sciences, α7 nicotinic receptor, MESH: Humans, MESH: Central Nervous System Agents, [SCCO.NEUR]Cognitive science/Neuroscience, Glutamate receptor, Tobacco Use Disorder, MESH: Central Nervous System Diseases, MESH: Schizophrenia, 3. Good health, MESH: Tobacco Use Disorder, Nicotinic agonist, medicine.anatomical_structure, chemistry, nervous system, Schizophrenia, Glutamate, Neuroscience, 030217 neurology & neurosurgery, MESH: Alzheimer Disease, Central Nervous System Agents
Abstract: International audience; Neuronal nicotinic acetylcholine receptors (nAChRs) play an important role in a variety of modulatory and regulatory processes including neurotransmitter release and synaptic transmission in various brain regions of the central nervous system (CNS). Glutamate is the principal excitatory neurotransmitter in the brain and the glutamatergic system participates in the pathophysiology of several neuropsychiatric disorders. Underpinning the importance of nAChRs, many studies demonstrated that nAChRs containing the α7 subunit facilitate glutamate release. Here, we review the currently available body of experimental evidence pertaining to α7 subunit containing nAChRs in their contribution to the modulation of glutamatergic neurotransmission, and we highlight the role of α7 in synaptic plasticity, the morphological and functional maturation of the glutamatergic system and therefore its important contribution in the modulation of neural circuits of the CNS.
Published: 2015

31. COB231 targets amyloid plaques in post-mortem human brain tissue and in an Alzheimer mouse model

Author: Martine Demeunynck, Catherine Ghezzi, M. Sallanon, Frank M. LaFerla, Dominique Garin, Danièle Marti-Battle, David Meyronet, Angélique Virgone-Carlotta, Michel Dubois-Dauphin, Pascale Perret, Philippe Millet, Bülent Gözel, Monique Touret, Sabine Chierici, Nathalie Streichenberger, Fatima Oukhatar, Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département de Chimie Moléculaire - Ingéniérie et Intéractions BioMoléculaires (DCM - I2BM), Département de Chimie Moléculaire (DCM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpitaux Universitaires de Genève (HUG), University of Geneva [Switzerland], Hospices Civils de Lyon (HCL), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure - Lyon (ENS 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), Département de pharmacochimie moléculaire (DPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Radiopharmaceutiques biocliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Radiopharmaceutiques Biocliniques, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Genève = University of Geneva (UNIGE), Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Perret, Pascale, and École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: Pathology, Hippocampus, Plaque, Amyloid, MESH: Microscopy, Fluorescence, Biochemistry, Mice, ddc:616.89, Image Processing, Computer-Assisted, MESH: Animals, Cellular localization, MESH: Proflavine, Brain, Human brain, MESH: Fluorescent Dyes, Immunohistochemistry, MESH: Image Processing, Computer-Assisted, MESH: Plaque, Amyloid, MESH: Staining and Labeling, medicine.anatomical_structure, Female, Autopsy, Proflavine, Genetically modified mouse, medicine.medical_specialty, Aminoacridine, Amyloid, MESH: Mice, Transgenic, Mice, Transgenic, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Biology, Sensitivity and Specificity, [SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Cellular and Molecular Neuroscience, MESH: Brain, In vivo, Alzheimer Disease, MESH: Mice, Inbred C57BL, medicine, Animals, Humans, Viability assay, MESH: Mice, Fluorescent Dyes, MESH: Humans, Staining and Labeling, MESH: Immunohistochemistry, MESH: Aminacrine, MESH: Sensitivity and Specificity, Mice, Inbred C57BL, Aminacrine, Disease Models, Animal, Microscopy, Fluorescence, MESH: Autopsy, MESH: Disease Models, Animal, MESH: Female, MESH: Alzheimer Disease
Abstract: International audience; Previous works have shown the interest of naturally fluorescent proflavine derivatives to label Abeta deposits in vitro. This study aimed to further characterize the properties of the proflavine 3-acetylamino-6-[3-(propargylamino)propanoyl]aminoacridine (COB231) derivative as a probe. This compound was therefore evaluated on human post-mortem and mice brain slices and in vivo in 18-month-old triple transgenic mice APPswe, PS1M146V and tauP301L (3xTgAD) mice presenting the main characteristics of Alzheimer's disease (AD). COB231 labelled amyloid plaques on brain slices of AD patients, and 3xTgAD mice at 10 and 0.1 μM respectively. However, no labelling of the neurofibrillary tangle-rich areas was observed either at high concentration or in the brain of fronto-temporal dementia patients. The specificity of this mapping was attested in mice using Thioflavin S and IMPY as positive controls of amyloid deposits. After intravenous injection of COB231 in old 3xTgAD mice, fluorescent amyloid plaques were detected in the cortex and hippocampus, demonstrating COB231 blood–brain barrier permeability. We also controlled the cellular localization of COB231 on primary neuronal cultures and showed that COB231 accumulates into the cytoplasm and not into the nucleus. Finally, using a viability assay, we only detected a slight cytotoxic effect of COB231 (< 10%) for the highest concentration (100 μM).
Published: 2015

32. Lifelong Endocrine Fluctuations and Related Cognitive Disorders

Author: Karen Ritchie, Marie-Laure Ancelin, Pathologies du système nerveux : recherche épidémiologique et clinique, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), and Villebrun, Dominique
Subjects: Male, Aging, MESH: Menopause, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Cognition, Disease, MESH: Neurotransmitter Agents, MESH: Estrogens, Cognition, 0302 clinical medicine, Drug Discovery, MESH: Puberty, MESH: Aging, 030212 general & internal medicine, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Neurotransmitter Agents, Sex Characteristics, MESH: Hormone Replacement Therapy, Cognitive disorder, Brain, MESH: Neuroprotective Agents, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Neuroprotective Agents, Female, Menopause, Alzheimer's disease, MESH: Sex Characteristics, Clinical psychology, Sex characteristics, Hormone Replacement Therapy, MESH: Brain, 03 medical and health sciences, Fetus, Alzheimer Disease, medicine, Humans, Dementia, Cognitive skill, Pharmacology, MESH: Humans, business.industry, Puberty, MESH: Fetus, Estrogens, medicine.disease, MESH: Male, MESH: Cognition Disorders, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Immunology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Verbal memory, Cognition Disorders, business, MESH: Female, MESH: Alzheimer Disease, 030217 neurology & neurosurgery
Abstract: International audience; The aim of this review is to examine the relationship between endocrine fluctuation and cognitive functioning. A plethora of in vitro and in vivo studies has demonstrated the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy (HRT) trials in non-demented post-menopausal women suggest a temporary positive effect (notably on verbal memory), and four recent meta-analyses converge to suggest a possible protective effect in relation to Alzheimer's disease (reducing risk by 29 to 44%). However, data from the only large randomised controlled trial published to date, the Women's Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT compared to controls. Several methodological differences between observation studies and controlled trials with regard to patient group, type, timing and duration of HRT, cognitive measures and analyses, are discussed to explain these discrepancies. The association between hormonal serum level and cognitive functioning remains controversial suggesting high inter-individual vulnerability in risk. Moreover, research on the impact of endocrine functioning on cognition during the female reproductive cycle suggests life-long fluctuations in vulnerability. Etiological models taking into account the interaction of clinical, reproductive, and menstrual events throughout life may provide a more valid approach in understanding the effects of steroids on the brain and in determining sub-groups at heightened risk. Cognitive disorders in the elderly are more likely be related to cumulated lifelong exposure to steroids, rather than to a specific exposure to a given steroid. Multifactorial models based on an exhaustive view of all hormonal events throughout reproductive life together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.
Published: 2005

33. Magnetic Resonance Imaging of the Neuroprotective Effect of Xaliproden in Rats

Author: Laurent Lemaire, Peter Keane, Jacqueline Fournier, Jean Vion-Dury, Sylviane Confort-Gouny, Yann Le Fur, Christian Ponthus, Patrick J. Cozzone, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Time Factors, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Pyridines, MESH: Rats, Sprague-Dawley, MESH: Magnetic Resonance Imaging, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, Hippocampus (mythology), MESH: Animals, Enzyme Inhibitors, MESH: Choline O-Acetyltransferase, 0303 health sciences, medicine.diagnostic_test, Brain, MESH: Naphthalenes, MESH: Neuroprotective Agents, General Medicine, Magnetic Resonance Imaging, Vincristine Injection, Neuroprotective Agents, MESH: Enzyme Inhibitors, Vincristine, Anesthesia, medicine.drug, MESH: Rats, MESH: Vincristine, Naphthalenes, Neuroprotection, Choline O-Acetyltransferase, MESH: Brain, 03 medical and health sciences, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Alzheimer Disease, medicine, Animals, Radiology, Nuclear Medicine and imaging, Xaliproden, 030304 developmental biology, business.industry, MESH: Pyridines, MESH: Time Factors, Magnetic resonance imaging, Rat brain, Mr imaging, MESH: Male, Rats, Disease Models, Animal, chemistry, MESH: Disease Models, Animal, business, MESH: Alzheimer Disease, 030217 neurology & neurosurgery
Abstract: RATIONALE AND OBJECTIVES. The neurotrophic effect of Xaliproden has been followed using sequential cerebral magnetic resonance imaging (MRI) in rats with vincristine-induced brain lesion as a model of Alzheimer disease. METHODS. Nineteen rats received an intraseptal injection of vincristine on day 0, followed by a daily gavage with either the vehicle (Tween-20 1%) (n = 10) or Xaliproden (10 mg/kg) (n = 9). Eight sham-operated controls received a daily gavage with either the vehicle (n = 4) or Xaliproden (n = 4). Brain MR imaging was performed at 4.7 T on a Biospec 47/30 MR system before surgery then 3, 7, 10, and 14 days after surgery. RESULTS. At day 3 following vincristine injection, an increase in MR signal intensity in the septum was observed on T2-weighted images. This increase was maximal at day 10, and remained stable until day 14. Daily treatment with Xaliproden delayed the appearance of hypersignals until day 7 and reduced by Ca. 50% the magnitude of the increase in signal intensity from day 10. No changes were observed in the hippocampus. CONCLUSION. Quantitative MRI objectifies noninvasively the neuroprotective effect of Xaliproden on rat brain anatomy.
Published: 2002

34. ALZHEIMER'S DISEASE AND VASCULAR FACTORS: FACTS AND THEORIES

Author: Pansari, K., Gupta, Anupam, Thomas, P., Indian Institute of Technology Bombay (IIT Bombay), Water Engineering and Management, Centre de Recherches sur les Très Basses Températures (CRTBT), Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Grenoble (INPG)-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de Neurosciences Fonctionnelles et Pathologies (LNFP), and Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH: Globus Pallidus, MESH: Psychiatry, MESH: Antigens, CD3, MESH: Comorbidity, MESH: Magnetic Resonance Imaging, MESH: Putamen, MESH: Basal Ganglia, MESH: Tourette Syndrome, MESH: Paraproteinemias, MESH: Neural Conduction, Risk Factors, MESH: Risk Factors, MESH: Child, MESH: Microcirculation, MESH: Caudate Nucleus, MESH: Aged, MESH: Polyneuropathies, MESH: Middle Aged, MESH: Vasculitis, General Medicine, MESH: Electrophysiologic Techniques, Cardiac, MESH: Immunoglobulin M, MESH: Review Literature as Topic, MESH: Conflict of Interest, Cardiovascular Diseases, MESH: Paraproteins, MESH: Great Britain, Female, MESH: Cerebrovascular Disorders, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Attention Deficit Disorder with Hyperactivity, MESH: Microscopy, Electron, MESH: Endothelium, MESH: Brain, MESH: Mononeuropathies, Alzheimer Disease, Humans, Aged, MESH: Lymphoma, B-Cell, MESH: Adolescent, MESH: Age Factors, MESH: Obsessive-Compulsive Disorder, MESH: Fascia, MESH: Humans, MESH: Cardiovascular Diseases, MESH: Adult, MESH: Male, Cerebrovascular Disorders, MESH: Drug Industry, MESH: Female, MESH: Alzheimer Disease
Abstract: International audience; Although Alzheimer s disease is classified as a neurodegenerative dementia, in Alzheimer s dementia there is increasing evidence of an association with vascular risk factors and vascular pathology. These observations are supported by epidemiological and pathological studies. Vascular factors may play a significant role in the pathogenesis of Alzheimer s dementia. Further research is needed to explore this relationship. Modification of vascular risk factors could make a significant impact towards prevention and treatment of Alzheimer s disease, which is a distressing and prevalent condition in the community. This article considers the relationship of these vascular risk factors and potential mechanisms associated with the aetiopathogenesis of Alzheimer s dementia.
Published: 2002

35. Protein aggregation and prionopathies

Author: Ronald Melki, Marianne Renner, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Laboratoire d'Enzymologie et Biochimie Structurales (LEBS), Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris
Subjects: Aging, Protein Conformation, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell, Drug Evaluation, Preclinical, Plaque, Amyloid, Disease, Protein aggregation, Prion Diseases, MESH: Neurodegenerative Diseases, Mice, Human health, Biopolymers, 0302 clinical medicine, MESH: Protein Conformation, MESH: Aging, MESH: Animals, MESH: Nerve Tissue Proteins, Amyotrophic lateral sclerosis, MESH: Amyotrophic Lateral Sclerosis, Inclusion Bodies, 0303 health sciences, MESH: Protein Aggregation, Pathological, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Neurodegenerative Diseases, Neurofibrillary Tangles, General Medicine, Endocytosis, 3. Good health, Cell biology, Crosstalk (biology), MESH: Biopolymers, MESH: Plaque, Amyloid, medicine.anatomical_structure, Biochemistry, MESH: Endocytosis, MESH: Drug Evaluation, Preclinical, MESH: Clinical Trials, Phase II as Topic, Prions, Nerve Tissue Proteins, Biology, Protein Aggregation, Pathological, 03 medical and health sciences, Clinical Trials, Phase II as Topic, MESH: Prions, Alzheimer Disease, Polysaccharides, Autophagy, medicine, Animals, Humans, MESH: Autophagy, Prion protein, MESH: Mice, 030304 developmental biology, MESH: Humans, Amyotrophic Lateral Sclerosis, MESH: Prion Diseases, medicine.disease, MESH: Inclusion Bodies, nervous system diseases, MESH: Solubility, Disease Models, Animal, MESH: Polysaccharides, Solubility, MESH: Disease Models, Animal, 030217 neurology & neurosurgery, MESH: Alzheimer Disease, MESH: Neurofibrillary Tangles
Abstract: International audience; Prion protein and prion-like proteins share a number of characteristics. From the molecular point of view, they are constitutive proteins that aggregate following conformational changes into insoluble particles. These particles escape the cellular clearance machinery and amplify by recruiting the soluble for of their constituting proteins. The resulting protein aggregates are responsible for a number of neurodegenerative diseases such as Creutzfeldt-Jacob, Alzheimer, Parkinson and Huntington diseases. In addition, there are increasing evidences supporting the inter-cellular trafficking of these aggregates, meaning that they are "transmissible" between cells. There are also evidences that brain homogenates from individuals developing Alzheimer and Parkinson diseases propagate the disease in recipient model animals in a manner similar to brain extracts of patients developing Creutzfeldt-Jacob's disease. Thus, the propagation of protein aggregates from cell to cell may be a generic phenomenon that contributes to the evolution of neurodegenerative diseases, which has important consequences on human health issues. Moreover, although the distribution of protein aggregates is characteristic for each disease, new evidences indicate the possibility of overlaps and crosstalk between the different disorders. Despite the increasing evidences that support prion or prion-like propagation of protein aggregates, there are many unanswered questions regarding the mechanisms of toxicity and this is a field of intensive research nowadays.
Published: 2014

36. Measuring cognitive change in subjects with prodromal Alzheimer's disease

Author: Cécile Proust-Lima, Hélène Jacqmin-Gadda, Thibault Mura, Bruno Dubois, Jacques Touchon, Tasnime N. Akbaraly, Claudine Berr, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département d'information médicale, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CIC - Montpellier, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Epidemiology and Public Health, University College of London [London] (UCL), Centre Mémoire Recherche Ressources MPL, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ministère de la santé PHRC national 2000, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, Mild Cognitive Impairment, Psychometrics, Prodromal Symptoms, Neuropsychological Tests, Sensitivity and Specificity, Benton Visual Retention Test, MESH: Aged, 80 and over, MESH: Psychometrics, Alzheimer Disease, medicine, cohort study, Humans, Verbal fluency test, Cognitive Dysfunction, Neuropsychological assessment, Cognitive neuropsychology in dementia, MESH: Prodromal Symptoms, Cognitive neuropsychology, Aged, Retrospective Studies, Aged, 80 and over, MESH: Aged, MESH: Humans, MESH: Middle Aged, medicine.diagnostic_test, Neuropsychology, Wechsler Adult Intelligence Scale, Cognition, MESH: Retrospective Studies, MESH: Mild Cognitive Impairment, MESH: Neuropsychological Tests, Middle Aged, Alzheimer's disease, MESH: Sensitivity and Specificity, MESH: Male, 3. Good health, Psychiatry and Mental health, neuropsychological assessment, Free recall, Female, Surgery, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Psychology, MESH: Female, MESH: Alzheimer Disease, Clinical psychology
Abstract: International audience; OBJECTIVE: To investigate the sensitivity of a large set of neuropsychological tests to detect cognitive changes due to prodromal Alzheimer's disease(AD); to compare their metrological properties in order to select a restricted number of these tests for the longitudinal follow-up of subjects with prodromal AD. PARTICIPANTS: 212 patients with mild cognitive impairment were tested at baseline by a standardised neuropsychological battery, which included: the Free and Cued Selective Reminding test (FCSRT), the Benton Visual Retention test, the Deno100, verbal fluency, a serial digit learning test, the double task of Baddeley, the Wechsler Adult Intelligence Scale (WAIS) similarities, the Trail-Making Test and the WAIS digit symbol test. Patients were monitored every 6 months for up to 3 years in order to identify those who converted to AD (retrospectively classified as prodromal AD). Statistical analyses were performed using a nonlinear multivariate mixed model involving a latent process. This model assumes that the psychometric tests are nonlinear transformations of a common latent cognitive process, and it captures the metrological properties of tests. RESULTS: 57 patients converted to AD. The most sensitive tests in the detection of cognitive changes due to prodromal AD were the FCSRT, the semantic verbal fluency and the Deno100. Some tests exhibited a higher sensitivity to cognitive changes for subjects with high levels of cognition, such as the free recall, delayed free recall scores of the FCSRT and the semantic verbal fluency, whereas others showed a higher sensitivity at low levels of cognition, such as the total recall score of the FCSRT. CONCLUSIONS: Tests used for the follow-up of prodromal AD subjects should be chosen among those that actually decline in this stage of the disease and should be selected according to the subject's initial scores.
Published: 2014

37. cdc-like/dual-specificity tyrosine phosphorylation-regulated kinases inhibitor leucettine L41 induces mTOR-dependent autophagy: implication for Alzheimer's disease

Author: Jean Pierre Bazureau, Gaëtan Chicanne, Xavier Fant, Assia Shisheva, Diego Sbrissa, Laurent Meijer, Bernard Payrastre, François Carreaux, Emilie Durieu, Emmanuelle Limanton, Phophorylation de protéines et Pathologies Humaines (P3H), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Physiology, Wayne State University [Detroit], Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), ManRos Therapeutics, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Simon, Marie Francoise
Subjects: MESH: Osteosarcoma, MESH: Tyrosine, Wortmannin, chemistry.chemical_compound, Mice, Phosphatidylinositol 3-Kinases, [CHIM] Chemical Sciences, MESH: Animals, MESH: Dioxoles, Enzyme Inhibitors, Phosphorylation, Phosphoinositide-3 Kinase Inhibitors, Osteosarcoma, Kinase, TOR Serine-Threonine Kinases, Imidazoles, Articles, Protein-Tyrosine Kinases, 3. Good health, Cell biology, MESH: Enzyme Inhibitors, Molecular Medicine, Microtubule-Associated Proteins, MESH: Imidazoles, MESH: Cell Line, Tumor, Context (language use), Dioxoles, Biology, Protein Serine-Threonine Kinases, BAG3, MESH: Protein-Tyrosine Kinases, MESH: Protein-Serine-Threonine Kinases, Cell Line, Alzheimer Disease, Cell Line, Tumor, Autophagy, Animals, Humans, MESH: Autophagy, [CHIM]Chemical Sciences, Phosphatidylinositol, MESH: Mice, PI3K/AKT/mTOR pathway, MESH: TOR Serine-Threonine Kinases, Pharmacology, MESH: Humans, MESH: Phosphorylation, Tyrosine phosphorylation, MESH: Cell Line, MESH: Microtubule-Associated Proteins, chemistry, MESH: Phosphatidylinositol 3-Kinases, Cancer research, Tyrosine, MESH: Alzheimer Disease
Abstract: International audience; Leucettines, a family of pharmacological inhibitors of dual-specificity tyrosine phosphorylation regulated kinases and cdc-like kinases (CLKs), are currently under investigation for their potential therapeutic application to Down syndrome and Alzheimer's disease. We here report that leucettine L41 triggers bona fide autophagy in osteosarcoma U-2 OS cells and immortalized mouse hippocampal HT22 cells, characterized by microtubule-associated protein light chain 3 membrane translocation and foci formation. Leucettine L41-triggered autophagy requires the Unc-51-like kinase and is sensitive to the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and 3-methyladenine, suggesting that it acts through the mammalian target of rapamycin (mTOR)/PI3K-dependent pathway. Leucettine L41 does not act by modifying the autophagic flux of vesicles. Leucettine L41-induced autophagy correlates best with inhibition of CLKs. Leucettine L41 modestly inhibited phosphatidylinositol-3-phosphate 5-kinase, FYVE domain-containing activity as tested both in vitro and in vivo, which may also contribute to autophagy induction. Altogether these results demonstrate that leucettines can activate the autophagic mTOR/PI3K pathway, a characteristic that may turn advantageous in the context of Alzheimer's disease treatment.
Published: 2014

38. SAP97-mediated ADAM10 trafficking from Golgi outposts depends on PKC phosphorylation

Author: Saraceno, C, Marcello, E, Di Marino, D, Borroni, B, Claeysen, S, Perroy, J, Padovani, A, Tramontano, A, Gardoni, F, Di Luca, M, Fondazione Cenci Bolognetti, Istituto Pasteur, BLANC - Les réseaux protéiques associés aux récepteurs 5 HT4 : gardes rapprochées du trafic de l'ADAM10 et de l'APP - - ADAMGUARD2012 - ANR-12-BSV4-0008 - BLANC - VALID, Cell permeable peptides as drug delivery system: a way towards innovative therapeutic strategies for neurodegeneration - CPADS - - EC:FP7:PEOPLE2008-03-01 - 2012-02-29 - 217902 - VALID, Department of Pharmacological Sciences and Biomolecular, Università degli Studi di Milano = University of Milan (UNIMI), Department of Physics [Roma La Sapienza], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), University of Brescia, Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Acknowledgement is made to the donors of the ADR, a program of the BrightFocus Foundation, for support of this research. This work was supported by grants from the European Union's Seventh Framework Program (FP7 2007-2013, Grant Agreement no. PIAP-GA-2008-217902) (to MdL), from Fondazione CARIPLO (project no. 2319-2008) (to MdL), from FIRB-Accordi di Programma (project code RBAP11HSZS) (to MdL), from PRIN 2010PWNJXK (to MdL), from Veronesi Foundation Young Investigator Research Programme 2013 (to EM), from the Alzheimer's Association (NIRP-14-304969) (to EM) and an ADR program research fellowship (to EM). SC acknowledges support from the France Alzheimer Association, the Languedoc Roussillon Region and the French Research National Agency ANR (ANR-12-BSV4-008-01 ADAMGUARD project)., ANR-12-BSV4-0008,ADAMGUARD,Les réseaux protéiques associés aux récepteurs 5 HT4 : gardes rapprochées du trafic de l'ADAM10 et de l'APP(2012), European Project: 217902,EC:FP7:PEOPLE,FP7-PEOPLE-2007-3-1-IAPP,CPADS(2008), University of Milan, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], 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), and Dipartimento di Fisica [Roma La Sapienza]
Subjects: Models, Molecular, MESH: Phosphothreonine, Golgi Apparatus, MESH: Amino Acid Sequence, MESH: Synapses, Discs Large Homolog 1 Protein, ADAM10 Protein, Chlorocebus aethiops, MESH: Animals, Phosphorylation, Protein Kinase C, MESH: COS Cells, Phosphothreonine, MESH: HEK293 Cells, COS Cells, MESH: Post-Synaptic Density, Original Article, MESH: Membrane Proteins, MESH: Models, Molecular, Protein Binding, MESH: ADAM Proteins, MESH: Enzyme Activation, MESH: Rats, Molecular Sequence Data, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Golgi Apparatus, Alzheimer Disease, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Adaptor Proteins, Signal Transducing, MESH: Adaptor Proteins, Signal Transducing, MESH: Humans, MESH: Molecular Sequence Data, MESH: Phosphorylation, Membrane Proteins, Post-Synaptic Density, MESH: Cercopithecus aethiops, MESH: Protein Kinase C, Rats, Enzyme Activation, ADAM Proteins, HEK293 Cells, MESH: Amyloid Precursor Protein Secretases, Synapses, Amyloid Precursor Protein Secretases, Cercopithecus aethiops, MESH: Alzheimer Disease
Abstract: International audience; A disintegrin and metalloproteinase 10 (ADAM10) is the major α-secretase that catalyzes the amyloid precursor protein (APP) ectodomain shedding in the brain and prevents amyloid formation. Its activity depends on correct intracellular trafficking and on synaptic membrane insertion. Here, we describe that in hippocampal neurons the synapse-associated protein-97 (SAP97), an excitatory synapse scaffolding element, governs ADAM10 trafficking from dendritic Golgi outposts to synaptic membranes. This process is mediated by a previously uncharacterized protein kinase C phosphosite in SAP97 SRC homology 3 domain that modulates SAP97 association with ADAM10. Such mechanism is essential for ADAM10 trafficking from the Golgi outposts to the synapse, but does not affect ADAM10 transport from the endoplasmic reticulum. Notably, this process is altered in Alzheimer's disease brains. These results help in understanding the mechanism responsible for the modulation of ADAM10 intracellular path, and can constitute an innovative therapeutic strategy to finely tune ADAM10 shedding activity towards APP.
Published: 2014

39. Measuring cognitive change in subjects with prodromal Alzheimer's disease

Author: Mura, Thibault, Proust-Lima, Cécile, Jacqmin-Gadda, Hélène, Akbaraly, Tasnime, Touchon, Jacques, Dubois, Bruno, Berr, Claudine, Villebrun, Dominique, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département d'information médicale, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CIC - Montpellier, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Epidemiology and Public Health, University College of London [London] (UCL), Centre Mémoire Recherche Ressources MPL, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Ministère de la santé PHRC national 2000
Subjects: MESH: Aged, Mild Cognitive Impairment, MESH: Humans, MESH: Middle Aged, MESH: Retrospective Studies, MESH: Mild Cognitive Impairment, MESH: Neuropsychological Tests, Alzheimer's disease, MESH: Sensitivity and Specificity, MESH: Male, neuropsychological assessment, MESH: Aged, 80 and over, MESH: Psychometrics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, cohort study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive neuropsychology in dementia, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Prodromal Symptoms, MESH: Female, MESH: Alzheimer Disease
Abstract: International audience; OBJECTIVE: To investigate the sensitivity of a large set of neuropsychological tests to detect cognitive changes due to prodromal Alzheimer's disease(AD); to compare their metrological properties in order to select a restricted number of these tests for the longitudinal follow-up of subjects with prodromal AD. PARTICIPANTS: 212 patients with mild cognitive impairment were tested at baseline by a standardised neuropsychological battery, which included: the Free and Cued Selective Reminding test (FCSRT), the Benton Visual Retention test, the Deno100, verbal fluency, a serial digit learning test, the double task of Baddeley, the Wechsler Adult Intelligence Scale (WAIS) similarities, the Trail-Making Test and the WAIS digit symbol test. Patients were monitored every 6 months for up to 3 years in order to identify those who converted to AD (retrospectively classified as prodromal AD). Statistical analyses were performed using a nonlinear multivariate mixed model involving a latent process. This model assumes that the psychometric tests are nonlinear transformations of a common latent cognitive process, and it captures the metrological properties of tests. RESULTS: 57 patients converted to AD. The most sensitive tests in the detection of cognitive changes due to prodromal AD were the FCSRT, the semantic verbal fluency and the Deno100. Some tests exhibited a higher sensitivity to cognitive changes for subjects with high levels of cognition, such as the free recall, delayed free recall scores of the FCSRT and the semantic verbal fluency, whereas others showed a higher sensitivity at low levels of cognition, such as the total recall score of the FCSRT. CONCLUSIONS: Tests used for the follow-up of prodromal AD subjects should be chosen among those that actually decline in this stage of the disease and should be selected according to the subject's initial scores.
Published: 2014

40. β-amyloid and ATP-induced diffusional trapping of astrocyte and neuronal metabotropic glutamate type-5 receptors

Author: Shrivastava, Amulya Nidhi, Kowalewski, Jacob M, Renner, Marianne, Bousset, Luc, Koulakoff, Annette, Melki, Ronald, Giaume, Christian, Triller, Antoine, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, 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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Enzymologie et Biochimie Structurales (LEBS), Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Time Factors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, Cell Communication, MESH: Rats, Sprague-Dawley, MESH: Animals, Newborn, Rats, Sprague-Dawley, Amyloid beta-Protein Precursor, Mice, Adenosine Triphosphate, MESH: Amyloid beta-Protein Precursor, MESH: Adenosine Triphosphate, MESH: Glial Fibrillary Acidic Protein, MESH: Animals, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, MESH: Receptor, Metabotropic Glutamate 5, Cerebral Cortex, Neurons, MESH: Statistics, Nonparametric, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Apyrase, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, MESH: Presenilin-1, MESH: Gene Expression Regulation, MESH: Amyloid beta-Peptides, Protein Transport, MESH: Calcium, MESH: Cells, Cultured, MESH: Apyrase, Amyloid, MESH: Protein Transport, MESH: Mutation, MESH: Rats, MESH: Mice, Transgenic, Receptor, Metabotropic Glutamate 5, Mice, Transgenic, Statistics, Nonparametric, MESH: Coculture Techniques, Alzheimer Disease, MESH: Mice, Inbred C57BL, Glial Fibrillary Acidic Protein, MESH: Cell Communication, Presenilin-1, Animals, Humans, MESH: Mice, MESH: Amyloid, Amyloid beta-Peptides, MESH: Humans, MESH: Time Factors, Coculture Techniques, MESH: Cerebral Cortex, Rats, Mice, Inbred C57BL, MESH: Astrocytes, Disease Models, Animal, Animals, Newborn, Gene Expression Regulation, Astrocytes, Mutation, Calcium, MESH: Disease Models, Animal, MESH: Alzheimer Disease
Abstract: β-Amyloid (Aβ) oligomers initiate synaptotoxicity following their interaction with the plasma membrane. Several proteins including metabotropic glutamate type 5 receptors (mGluR5s) contribute to this process. We observed an overexpression of mGluR5s in reactive astrocytes surrounding Aβ plaques in brain sections from an Alzheimer's disease mouse model. In a simplified cell culture system, using immunocytochemistry and single molecule imaging, we demonstrated a rapid binding of Aβ oligomers on the plasma membrane of astrocytes. The resulting aggregates of Aβ oligomers led to the diffusional trapping and clustering of mGluR5s. Further, Aβ oligomers induced an increase in ATP release following activation of astroglial mGluR5s by its agonist. ATP slowed mGluR5s diffusion in astrocytes as well as in neurons co-cultured with astrocytes. This effect, which is purinergic receptor-dependent, was not observed in pure neuronal cultures. Thus, Aβ oligomer- and mGluR5-dependent ATP release by astrocytes may contribute to the overall deleterious effect of mGluR5s in Alzheimer's disease. GLIA 2013;61:1673-1686.
Published: 2013

41. α-Secretase-derived fragment of cellular prion, N1, protects against monomeric and oligomeric amyloid β (Aβ)-associated cell death

Author: Claire Sunyach, Charlotte Bauer, Sergio T. Ferreira, Aurelie Thevenet, Marie-Victoire Guillot-Sestier, Maria Paz Marzolo, Frédéric Checler, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Millennium Nucleus for Regenerative Biology (MINREB), and Pontificia Universidad Católica de Chile (UC)
Subjects: p53, MESH: Cell Death, MESH: Neurons, MESH: Cricetinae, Biochemistry, Transactivation, Aβ Oligomers, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, MESH: Cricetulus, MESH: Amyloid beta-Protein Precursor, Cricetinae, MESH: Caspase 3, Amyloid precursor protein, MESH: Animals, Enzyme Inhibitors, Neurons, 0303 health sciences, biology, Cell Death, MESH: Peptides, MESH: Protein Multimerization, Caspase 3, Chinese hamster ovary cell, 030302 biochemistry & molecular biology, Molecular Bases of Disease, Cell biology, MESH: Enzyme Inhibitors, MESH: HEK293 Cells, Secretases, Additions and Corrections, Alzheimer's disease, sAPPα, Programmed cell death, Amyloid, MESH: Enzyme Activation, Prions, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, CHO Cells, 03 medical and health sciences, Cricetulus, MESH: CHO Cells, Alzheimer Disease, medicine, Animals, Humans, MESH: PrPC Proteins, PrPC Proteins, N1 Fragment, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Humans, HEK 293 cells, Cell Biology, medicine.disease, Staurosporine, Enzyme Activation, HEK293 Cells, MESH: Amyloid Precursor Protein Secretases, biology.protein, MESH: Staurosporine, Amyloid Precursor Protein Secretases, Protein Multimerization, Peptides, Amyloid precursor protein secretase, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract: International audience; In physiological conditions, both β-amyloid precursor protein (βAPP) and cellular prion (PrP(c)) undergo similar disintegrin-mediated α-secretase cleavage yielding N-terminal secreted products referred to as soluble amyloid precursor protein-α (sAPPα) and N1, respectively. We recently demonstrated that N1 displays neuroprotective properties by reducing p53-dependent cell death both in vitro and in vivo. In this study, we examined the potential of N1 as a neuroprotector against amyloid β (Aβ)-mediated toxicity. We first show that both recombinant sAPPα and N1, but not its inactive parent fragment N2, reduce staurosporine-stimulated caspase-3 activation and TUNEL-positive cell death by lowering p53 promoter transactivation and activity in human cells. We demonstrate that N1 also lowers toxicity, cell death, and p53 pathway exacerbation triggered by Swedish mutated βAPP overexpression in human cells. We designed a CHO cell line overexpressing the London mutated βAPP (APP(LDN)) that yields Aβ oligomers. N1 protected primary cultured neurons against toxicity and cell death triggered by oligomer-enriched APP(LDN)-derived conditioned medium. Finally, we establish that N1 also protects neurons against oligomers extracted from Alzheimer disease-affected brain tissues. Overall, our data indicate that a cellular prion catabolite could interfere with Aβ-associated toxicity and that its production could be seen as a cellular protective mechanism aimed at compensating for an sAPPα deficit taking place at the early asymptomatic phase of Alzheimer disease.
Published: 2013

42. The emerging role of SHANK genes in neuropsychiatric disorders

Author: Guilmatre, Audrey, Huguet, Guillaume, Delorme, Richard, Bourgeron, Thomas, Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur, the Bettencourt-Schueller Foundation, CNRS, University Paris Diderot, Neuron-ERANET (EUHF-AUTISM), the Fondation de France, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Orange Foundation, and the Fondamental Foundation, ANR. Grant Number: ANR-08-MNPS-037-01—SynGen, ANR-08-MNPS-0037,SynGen-ASD-LD,Genes synaptiques de l'autisme et du retard mental(2008), ANR-10-NEUR-0003,EUHFAUTISM(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Gènes, Synapses et Cognition
Subjects: SHANK, MESH: Mutation, Bipolar Disorder, MESH: Chromosome Deletion, [SDV]Life Sciences [q-bio], Chromosomes, Human, Pair 22, Chromosome Disorders, Nerve Tissue Proteins, MESH: Child Development Disorders, Pervasive, [SCCO]Cognitive science, Alzheimer Disease, MESH: Bipolar Disorder, MESH: Mental Disorders, Animals, Humans, MESH: Animals, MESH: Nerve Tissue Proteins, MESH: Chromosomes, Human, Pair 22, MESH: Chromosome Disorders, MESH: Humans, Mental Disorders, MESH: Schizophrenia, body regions, neuropsychiatric disorders, Child Development Disorders, Pervasive, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Mutation, Schizophrenia, Phelan-McDermid syndrome, Chromosome Deletion, MESH: Alzheimer Disease
Abstract: International audience; The genetic heterogeneity of neuropsychiatric disorders is high, but some pathways emerged, notably synaptic functioning. A large number of mutations have been described in genes such as neuroligins, neurexins, and SHANK that play a role in the formation and the maintenance of synapses. This review focuses on the disorders associated with mutations in SHANK3 and the other members of its family, SHANK1 and SHANK2. SHANKs are scaffolding proteins of the postsynaptic density of glutamatergic synapses. SHANK3 has been described in the Phelan-McDermid syndrome (PMS), but also in autism spectrum disorders (ASD) and schizophrenia associated to moderate to severe intellectual disability (ID) and poor language. The evolution of patients with PMS includes symptoms of bipolar disorder and regression. SHANK2 has been identified in patients with ASD with mild to severe ID. SHANK1 has been associated with high-functioning autism in male patients, while carrier females only display anxiety and shyness. Finally, based on neuropathological findings in animal models and patients, a possible role of SHANK in Alzheimer's disease is discussed. Altogether, this review describes the clinical trajectories associated with different mutations of the SHANK genes and provides information to further investigate the role of the SHANK genes in neuropsychiatric disorders.
Published: 2013

43. Alzheimer disease: Aβ-independent processes-rethinking preclinical AD

Author: Chételat, Gaël, Neuropsychologie cognitive et neuroanatomie fonctionnelles de la mémoire humaine, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études ( EPHE ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Eustache, Francis
Subjects: MESH : Alzheimer Disease, MESH : Amyloid beta-Peptides, Article, MESH : Cognition Disorders, MESH: Brain, Alzheimer Disease, mental disorders, Humans, MESH: Amyloidosis, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Humans, Amyloid beta-Peptides, MESH : Brain Injuries, MESH : Humans, Brain, Amyloidosis, MESH: Amyloid beta-Peptides, MESH : Amyloidosis, MESH: Cognition Disorders, MESH : Brain, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Brain Injuries, MESH: Brain Injuries, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognition Disorders, MESH: Alzheimer Disease
Abstract: International audience; The amyloid cascade hypothesis, which posits that amyloid-β accumulation is the key event in Alzheimer disease neurodegeneration, has dominated the field for 20 years. Recent findings, however, show that neuronal-injury biomarkers are independent of amyloid-β, calling for reconsideration of the pathological cascade and assessment of alternative therapeutic strategies.
Published: 2013

44. Characterization of mitochondrial dysfunction in the 7PA2 cell model of Alzheimer's disease

Author: Giovanni Meli, Marzia Arese, Annalisa Manca, Paolo Sarti, Maria Chiara Magnifico, Antonino Cattaneo, Alessandro Giuffrè, Nina Krako, Elena Forte, Daniela Mastronicola, Agnese Lecci, Scuola Normale Superiore di Pisa (SNS), European Brain Research Institute [Rome, Italy] (EBRI), Department of Biochemical Sciences 'Rossi Fanelli', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], CNR - National Research Council of Italy, Institute of Molecular Biology and Pathology, Krako, N, Magnifico, Mc, Arese, M, Meli, G, Forte, E, Lecci, A, Manca, A, Giuffrè, A, Mastronicola, D, Sarti, P, and Cattaneo, Antonino
Subjects: Bioenergetics, Respiratory chain, MESH: Cricetinae, bioenergetics, 0302 clinical medicine, MESH: Cricetulus, Cricetinae, Glycolysis, MESH: Animals, MESH: Oxygen Consumption, alzheimer's disease, mitochondrial dysfunction, chemistry.chemical_classification, 0303 health sciences, General Neuroscience, Chinese hamster ovary cell, MESH: Reactive Oxygen Species, General Medicine, Alzheimer's disease, Warburg effect, MESH: Amyloid beta-Peptides, Mitochondria, Psychiatry and Mental health, Clinical Psychology, Biochemistry, amyloid-beta oligomers, MESH: Mitochondria, amyloid-β oligomer, Oxidative phosphorylation, CHO Cells, Biology, Cell Line, 03 medical and health sciences, Cricetulus, Oxygen Consumption, Alzheimer Disease, MESH: CHO Cells, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Reactive oxygen species, Amyloid beta-Peptides, MESH: Humans, [SCCO.NEUR]Cognitive science/Neuroscience, bioenergetic, Molecular biology, MESH: Cell Line, chemistry, Cell culture, Geriatrics and Gerontology, Reactive Oxygen Species, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract: The 7WD4 and 7PA2 cell lines, widely used as cellular models for Alzheimer's disease (AD), have been used to investigate the effects of amyloid-beta protein precursor overexpression and amyloid-beta (A beta) oligomer accumulation on mitochondrial function. Under standard culture conditions, both cell lines, compared to Chinese hamster ovary (CHO) control cells, displayed an similar to 5% decrease of O-2 respiration as sustained by endogenous substrates. Functional impairment of the respiratory chain was found distributed among the protein complexes, though more evident at the level of complex I and complex IV. Measurements of ATP showed that its synthesis by oxidative phosphorylation is decreased in 7WD4 and 7PA2 cells by similar to 25%, this loss being partly compensated by glycolysis (Warburg effect). Compensation proved to be more efficient in 7WD4 than in 7PA2 cells, the latter cell line displaying the highest reactive oxygen species production. The strongest deficit was observed in mitochondrial membrane potential that is almost 40% and 60% lower in 7WD4 and 7PA2 cells, respectively, in comparison to CHO controls. All functional parameters point to a severe bioenergetic impairment of the AD cells, with the extent of mitochondrial dysfunction being correlated to the accumulation of A beta peptides and oligomers.
Published: 2013

45. Simultaneous measurement of amyloid fibril formation by dynamic light scattering and fluorescence reveals complex aggregation kinetics

Author: Ron R. Kopito, Yannick Sourigues, Ronald Melki, Aaron M. Streets, Stephen R. Quake, Stanford University, Laboratoire d'Enzymologie et Biochimie Structurales (LEBS), and Centre National de la Recherche Scientifique (CNRS)
Subjects: Macromolecular Assemblies, Light, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Protein Structure, Secondary, lcsh:Medicine, 02 engineering and technology, MESH: Amino Acid Sequence, Biochemistry, Protein Structure, Secondary, Light scattering, Polymerization, chemistry.chemical_compound, Protein structure, lcsh:Science, Condensed-Matter Physics, Peptide sequence, 0303 health sciences, Multidisciplinary, MESH: Kinetics, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Physics, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Parkinson Disease, 021001 nanoscience & nanotechnology, MESH: Amyloid beta-Peptides, Chemistry, Huntington Disease, Autosomal Dominant, Thioflavin, 0210 nano-technology, Research Article, Amyloid, Protein Structure, Protein subunit, Biophysics, MESH: Thiazoles, macromolecular substances, Fibril, Fluorescence, 03 medical and health sciences, Dynamic light scattering, Alzheimer Disease, mental disorders, Genetics, Humans, Amino Acid Sequence, Benzothiazoles, MESH: Particle Size, Particle Size, Protein Interactions, Biology, 030304 developmental biology, MESH: Amyloid, Amyloid beta-Peptides, MESH: Humans, MESH: Fluorescence, lcsh:R, Proteins, Human Genetics, Optics, Polymer Chemistry, MESH: Huntington Disease, MESH: Light, Kinetics, Thiazoles, chemistry, Phase Transformation, lcsh:Q, MESH: Alzheimer Disease, MESH: Parkinson Disease
Abstract: International audience; An apparatus that combines dynamic light scattering and Thioflavin T fluorescence detection is used to simultaneously probe fibril formation in polyglutamine peptides, the aggregating subunit associated with Huntington's disease, in vitro. Huntington's disease is a neurodegenerative disorder in a class of human pathologies that includes Alzheimer's and Parkinson's disease. These pathologies are all related by the propensity of their associated protein or polypeptide to form insoluble, β-sheet rich, amyloid fibrils. Despite the wide range of amino acid sequence in the aggregation prone polypeptides associated with these diseases, the resulting amyloids display strikingly similar physical structure, an observation which suggests a physical basis for amyloid fibril formation. Thioflavin T fluorescence reports β-sheet fibril content while dynamic light scattering measures particle size distributions. The combined techniques allow elucidation of complex aggregation kinetics and are used to reveal multiple stages of amyloid fibril formation.
Published: 2013

46. MRI, FDG-TEP and Florbetapir-TEP in AD

Author: La Joie , Renaud, Perrotin , Audrey, Barre , Louisa, Hommet , Caroline, Mézenge , Florence, Ibazizene , Méziane, Camus , Vincent, Landeau , Brigitte, GUILLOTEAU , Denis, De La Sayette , Vincent, Eustache , Francis, Desgranges , Beatrice, Gaël , Chételat, Neuropsychologie cognitive et neuroanatomie fonctionnelles de la mémoire humaine, Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -École pratique des hautes études ( EPHE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Développements Méthodologiques en Tomographie par Emission de Positions ( LDM-TEP ), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales ( ISTCT ), Normandie Université ( NU ) -Normandie Université ( NU ) -Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Centre Mémoire Ressources Recherche ( CMRR ), Hôpital Bretonneau-CHRU Tours, Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Clinique Psychiatrique Universitaire, CHRU Tours, Laboratoire de Médecine Nucléaire, Unité de Neurologie Générale ( UNG ), CHU Caen-Pôle Neuro-Cardio Sciences et Urgences, This study was funded by Agence Nationale de la Recherche (ANR LONGVIE 2007), Programme Hospitalier de Recherche Clinique (PHRC National 2008), Région Basse Normandie, and Institut National de la Santé et de la Recherche Médicale (Inserm), including the Inserm Liliane Bettencourt School (MD-PhD Program)., Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Développements Méthodologiques en Tomographie par Emission de Positons (LDM-TEP), 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-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Centre Mémoire Ressources Recherche (CMRR), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)
Subjects: MESH: Hippocampus, MESH : Male, MESH : Aged, MESH : Alzheimer Disease, MESH : Brain Chemistry, MESH: Atrophy, MESH : Hippocampus, MESH : Amyloid beta-Peptides, MESH: Magnetic Resonance Imaging, MESH : Magnetic Resonance Imaging, MESH : Neuroimaging, MESH : Female, MESH: Neuroimaging, MESH: Brain Chemistry, MESH : Atrophy, MESH: Aged, MESH: Humans, MESH : Humans, MESH: Biological Markers, MESH : Positron-Emission Tomography, MESH: Neuropsychological Tests, MESH: Image Processing, Computer-Assisted, MESH: Male, MESH: Positron-Emission Tomography, MESH: Amyloid beta-Peptides, MESH : Neuropsychological Tests, MESH : Biological Markers, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Neurofibrillary Tangles, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Educational Status, MESH: Female, MESH: Alzheimer Disease, MESH : Image Processing, Computer-Assisted, MESH : Educational Status, MESH: Neurofibrillary Tangles
Abstract: International audience; Gray matter atrophy, glucose hypometabolism, and β-amyloid Aβ deposition are well-described hallmarks of Alzheimer's disease, but their relationships are poorly understood. The present study aims to compare the local levels of these three alterations in humans with Alzheimer's disease. Structural magnetic resonance imaging, (18)F-fluorodeoxyglucose positron emission tomography (PET), and (18)F-florbetapir PET data from 34 amyloid-negative healthy controls and 20 demented patients with a high probability of Alzheimer's disease etiology (attested using neuroimaging biomarkers as recently recommended) were analyzed. For each patient and imaging modality, age-adjusted Z-score maps were computed, and direct between-modality voxelwise comparison and correlation analyses were performed. Significant differences in the levels of atrophy, hypometabolism, and Aβ deposition were found in most brain areas, but the hierarchy differed across regions. A cluster analysis revealed distinct subsets of regions: (1) in the hippocampus, atrophy exceeded hypometabolism, whereas Aβ load was minimal; (2) in posterior association areas, Aβ deposition was predominant, together with high hypometabolism and lower but still significant atrophy; and (3) in frontal regions, Aβ deposition was maximal, whereas structural and metabolic alterations were low. Atrophy and hypometabolism significantly correlated in the hippocampus and temporo-parietal cortex, whereas Aβ load was not significantly related to either atrophy or hypometabolism. These findings provide direct evidence for regional variations in the hierarchy and relationships between Aβ load, hypometabolism, and atrophy. Altogether, these variations probably reflect the differential involvement of region-specific pathological or protective mechanisms, such as the presence of neurofibrillary tangles, disconnection, as well as compensation processes.
Published: 2012

47. Distinct patterns of antiamyloid-β antibodies in typical and atypical Alzheimer disease

Author: Edmond Moukari, Stéphane Lehéricy, Michel Bottlaender, Bruno Dubois, Olivier Colliot, Leonardo Cruz de Souza, Foudil Lamari, Guillaume Dorothée, Marie Chupin, Pierre Aucouturier, Fabian Corlier, Marie Sarazin, Renaud Maroy, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Système immunitaire et neuroinflammation [CRSA], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Service Hospitalier Frédéric Joliot (SHFJ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie, CHU Saint-Antoine [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)-Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Pathology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cerebral disorder, Subclass, Immunoglobulin G, 0302 clinical medicine, Cerebrospinal fluid, MESH: Aged, 80 and over, MESH: Radionuclide Imaging, Phosphorylation, Central nervous system disease, Aged, 80 and over, MESH: Aged, MESH: Immunoglobulin G, 0303 health sciences, MESH: Middle Aged, Brain, Middle Aged, MESH: Amyloid beta-Peptides, MESH: Immunoglobulin M, 3. Good health, MESH: tau Proteins, Alzheimer's disease, Antibody, Alzheimer disease, medicine.medical_specialty, Amyloid, tau Proteins, Biology, Antibodies, 03 medical and health sciences, MESH: Brain, Arts and Humanities (miscellaneous), Antigen, medicine, Humans, Radionuclide Imaging, Aged, 030304 developmental biology, Amyloid beta-Peptides, MESH: Humans, MESH: Phosphorylation, MESH: Antibodies, Posterior cortical atrophy, medicine.disease, Nervous system diseases, MESH: Male, Immunoglobulin M, Degenerative disease, Immunology, biology.protein, MESH: Biomarkers, Neurology (clinical), Biomarkers, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract: International audience; OBJECTIVE: To compare serum antiamyloid-β (Aβ) antibodies in typical and atypical Alzheimer disease (AD). DESIGN: Preliminary observations. SUBJECTS: Thirteen patients with AD, 8 patients with posterior cortical atrophy with evidence of AD (PCA-AD) pathophysiological process by both cerebrospinal fluid (CSF) biomarkers and amyloid imaging, and 12 age-matched control individuals. INTERVENTIONS: The class and subclass levels of serum anti-Aβ antibodies were measured using an oligomer-based enzyme-linked immunosorbent assay. This method allowed measuring both free antibodies and, after acidic treatment, the total fraction that includes all antibodies complexed with circulating Aβ40/42 and any cross-reacting antigen. RESULTS: Anti-Aβ IgG were restricted to the IgG1 and IgG3 subclasses. Their total levels were strikingly lower and more homogeneous in patients with PCA compared with both typical AD and controls, while biomarkers of amyloid deposition (CSF Aβ42 and positron emission tomography amyloid imaging) were similar in patients with AD and patients with PCA. CONCLUSIONS: Serum anti-Aβ IgG1 and IgG3 antibodies differ between distinct forms of AD. Its significance is discussed for possible implications as immune effectors in the specific pathophysiology of AD variants.
Published: 2012

48. Towards understanding the phosphorylation code of tau

Author: Laziza Amniai, Arnaud Leroy, Guy Lippens, Alain Sillen, Isabelle Landrieu, Jean Michel Wieruszeski, Université Lille Nord de France (COMUE), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie Appliquée, Université Paris-Sud - Paris 11 (UP11), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: inorganic chemicals, Magnetic Resonance Spectroscopy, Tau protein, tau Proteins, macromolecular substances, Biochemistry, environment and public health, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Alzheimer Disease, medicine, Animals, Humans, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylation, 030304 developmental biology, 0303 health sciences, MESH: Humans, biology, MESH: Phosphorylation, Chemistry, Kinase, MESH: Magnetic Resonance Spectroscopy, Nuclear magnetic resonance spectroscopy, medicine.disease, In vitro, Cell biology, MESH: tau Proteins, enzymes and coenzymes (carbohydrates), Recombinant DNA, biology.protein, bacteria, Alzheimer's disease, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract: International audience; We describe our efforts to combine in vitro enzymatic reactions with recombinant kinases to phosphorylate the neuronal tau protein, and NMR spectroscopy to unravel the resulting phosphorylation pattern in both qualitative and quantitative manners. This approach, followed by functional assays with the same samples, gives access to the complex phosphorylation code of tau. As a result, we propose a novel hypothesis for the link between tau (hyper)phosphorylation and aggregation.
Published: 2012

49. Emotional decoding abilities in Alzheimer's disease: a meta-analysis

Author: Yanica Klein-Koerkamp, Pascal Hot, Marine Beaudoin, Monica Baciu, Laboratoire de Psychologie et NeuroCognition (LPNC), Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Laboratoire Inter-universitaire de Psychologie : Personnalité, Cognition, Changement Social (LIP-PC2S), and Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])
Subjects: MESH: Facial Expression, Emotions, MESH: Social Perception, [SHS.PSY]Humanities and Social Sciences/Psychology, Disease, Neuropsychological Tests, Developmental psychology, 0302 clinical medicine, Cognitive decline, ComputingMilieux_MISCELLANEOUS, Depression (differential diagnoses), MESH: Publication Bias, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Depression, General Neuroscience, 05 social sciences, MESH: Neuropsychological Tests, General Medicine, Facial Expression, Psychiatry and Mental health, Clinical Psychology, MESH: Photic Stimulation, Social Perception, Meta-analysis, Data Interpretation, Statistical, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Psychology, Clinical psychology, MESH: Depression, MESH: Psychomotor Performance, Emotional processing, Affect (psychology), 050105 experimental psychology, 03 medical and health sciences, Disease severity, Alzheimer Disease, medicine, Humans, 0501 psychology and cognitive sciences, Cognitive Dysfunction, Cognitive deficit, MESH: Emotions, MESH: Humans, MESH: Mild Cognitive Impairment, Geriatrics and Gerontology, MESH: Data Interpretation, Statistical, Publication Bias, MESH: Alzheimer Disease, 030217 neurology & neurosurgery, Photic Stimulation, Psychomotor Performance
Abstract: International audience; Studies on emotional processing in Alzheimer's disease (AD) have reported abnormalities in emotional decoding. However, it remains unclear whether the impairment depends on a general cognitive decline that characterizes these patients or is an independent deficit. We conducted a comprehensive meta-analysis of existing studies that compared AD patients with age-matched healthy older adults (HOA) on measures of emotional decoding abilities. Our first goal was to quantify the magnitude of the AD patients' deficit. The second goal was to identify variables that may modulate the deficit, including emotional task design and participants' characteristics. The random-effects model analysis on 212 effect sizes indicated that AD patients showed significant impairment in emotional decoding abilities. This deficit is consistent regardless of the emotional task, stimuli, type of emotion considered, or disease severity. After we controlled for cognitive status, the emotional performance in AD patients was still poorer than that in HOA. The effect size of emotional performance was significantly lower when the cognitive status was considered than when it was not. Thus, our results suggest that impaired emotion processing in AD patients cannot be solely explained by the cognitive deficit. These findings provide evidence that progressive neuropathological changes characterizing the disease could affect emotional processing, which may suggest that clinicians should be sensitive to the emergence of impairments in emotional decoding. Further research that addresses the limitations of existing studies is needed to draw conclusions about methodological issues and the impact of the AD patient's depression symptoms on emotional decoding.
Published: 2012

50. Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease

Author: Monica Di Luca, Alerie Guzman de la Fuente, Stefano Musardo, Barbara Borroni, Hugo Vara, Alessandro Padovani, Maurizio Giustetto, Isabel Pérez-Otaño, Silvia Pelucchi, Daniele Di Marino, Claudia Saraceno, Fabrizio Gardoni, Anna Tramontano, Elena Marcello, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano [Milano] (UNIMI), Dipartimento di Neuroscienza, Università degli studi di Torino (UNITO), Department of Physics [Roma La Sapienza], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Dipartimento di Scienze Neurologiche, Università degli Studi di Brescia [Brescia], Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Centro de Investigaciòn Mèdica Aplicada, Universidad de Navarra, and This work was supported by funding from the European Union’s Seventh Framework Program (FP7 2007-2013) under Grant Agreement no. PIAP-GA-2008-217902 to M. Di Luca, from Fondazione CARIPLO (project number 2319-2008) to M. Di Luca, from FIRB-Accordi di Programma, project code RBAP11HSZS to M. Di Luca, from PRIN 2010-2011 2010PWNJXK to M. Di Luca, from the Italian Institute of Technology SEED project to A. Tramontano.
Subjects: Models, Molecular, MESH: Hippocampus, MESH: Long-Term Synaptic Depression, ADAM10, Amino Acid Motifs, Long-Term Potentiation, MESH: Amino Acid Sequence, Alzheimer's Disease, Hippocampus, MESH: Synapses, Synapse, Discs Large Homolog 1 Protein, MESH: Amino Acid Motifs, ADAM10 Protein, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, Postsynaptic potential, MESH: Amyloid beta-Protein Precursor, Chlorocebus aethiops, Protein Interaction Mapping, MESH: Animals, DENDRITIC SPINES, LTP, Electrophysiology, synapses, Synaptic plasticity, MESH: Neuronal Plasticity, 0303 health sciences, Neuronal Plasticity, biology, Long-term potentiation, General Medicine, Endocytosis, Cell biology, MESH: COS Cells, Protein Transport, MESH: Endocytosis, COS Cells, Excitatory postsynaptic potential, MESH: Membrane Proteins, MESH: Models, Molecular, Protein Binding, Research Article, MESH: ADAM Proteins, MESH: Protein Transport, Molecular Sequence Data, Fatty Acid-Binding Proteins, MESH: Fatty Acid-Binding Proteins, Clathrin, 03 medical and health sciences, MESH: Long-Term Potentiation, Alzheimer Disease, MESH: Protein Binding, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein Interaction Domains and Motifs, Amino Acid Sequence, MESH: Mice, MESH: Adaptor Proteins, Signal Transducing, 030304 developmental biology, Adaptor Proteins, Signal Transducing, MESH: Protein Interaction Domains and Motifs, MESH: Humans, MESH: Molecular Sequence Data, [SCCO.NEUR]Cognitive science/Neuroscience, Long-Term Synaptic Depression, MESH: Protein Interaction Mapping, Cell Membrane, Membrane Proteins, MESH: Cercopithecus aethiops, ADAM Proteins, MESH: Amyloid Precursor Protein Secretases, Membrane protein, Synapses, biology.protein, Amyloid Precursor Protein Secretases, MESH: Alzheimer Disease, 030217 neurology & neurosurgery, MESH: Cell Membrane
Abstract: International audience; A disintegrin and metalloproteinase 10 (ADAM10), a disintegrin and metalloproteinase that resides in the postsynaptic densities (PSDs) of excitatory synapses, has previously been shown to limit β-amyloid peptide (Aβ) formation in Alzheimer's disease (AD). ADAM10 also plays a critical role in regulating functional membrane proteins at the synapse. Using human hippocampal homogenates, we found that ADAM10 removal from the plasma membrane was mediated by clathrin-dependent endocytosis. Additionally, we identified the clathrin adaptor AP2 as an interacting partner of a previously uncharacterized atypical binding motif in the ADAM10 C-terminal domain. This domain was required for ADAM10 endocytosis and modulation of its plasma membrane levels. We found that the ADAM10/AP2 association was increased in the hippocampi of AD patients compared with healthy controls. Long-term potentiation (LTP) in hippocampal neuronal cultures induced ADAM10 endocytosis through AP2 association and decreased surface ADAM10 levels and activity. Conversely, long-term depression (LTD) promoted ADAM10 synaptic membrane insertion and stimulated its activity. ADAM10 interaction with the synapse-associated protein-97 (SAP97) was necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced changes in spine morphogenesis. These data identify and characterize a mechanism controlling ADAM10 localization and activity at excitatory synapses that is relevant to AD pathogenesis.
Published: 2012

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