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1. Plasma Proteomic Analysis Distinguishes Severity Outcomes of Human Ebola Virus Disease

Author

Arthur Viodé, Kinga K. Smolen, Benoit Fatou, Zainab Wurie, Patrick Van Zalm, Mandy Kader Konde, Balla Moussa Keita, Richard Amento Ablam, Eleanor N. Fish, and Hanno Steen

Subjects
Ebola virus disease, interferon, plasma proteome, mass spectrometry, Ebola virus, Microbiology, QR1-502
Abstract

ABSTRACT Ebola virus (EBV) disease (EVD) is a highly virulent systemic disease characterized by an aggressive systemic inflammatory response and impaired vascular and coagulation systems, often leading to uncontrolled hemorrhaging and death. In this study, the proteomes of 38 sequential plasma samples from 12 confirmed EVD patients were analyzed. Of these 12 cases, 9 patients received treatment with interferon beta 1a (IFN-β-1a), 8 survived EVD, and 4 died; 2 of these 4 fatalities had received IFN-β-1a. Our analytical strategy combined three platforms targeting different plasma subproteomes: a liquid chromatography-mass spectrometry (LC-MS)-based analysis of the classical plasma proteome, a protocol that combines the depletion of abundant plasma proteins and LC-MS to detect less abundant plasma proteins, and an antibody-based cytokine/chemokine multiplex assay. These complementary platforms provided comprehensive data on 1,000 host and viral proteins. Examination of the early plasma proteomes revealed protein signatures that differentiated between fatalities and survivors. Moreover, IFN-β-1a treatment was associated with a distinct protein signature. Next, we examined those proteins whose abundances reflected viral load measurements and the disease course: resolution or progression. Our data identified a prognostic 4-protein biomarker panel (histone H1-5, moesin, kininogen 1, and ribosomal protein L35 [RPL35]) that predicted EVD outcomes more accurately than the onset viral load. IMPORTANCE As evidenced by the 2013–2016 outbreak in West Africa, Ebola virus (EBV) disease (EVD) poses a major global health threat. In this study, we characterized the plasma proteomes of 12 individuals infected with EBV, using two different LC-MS-based proteomics platforms and an antibody-based multiplexed cytokine/chemokine assay. Clear differences were observed in the host proteome between individuals who survived and those who died, at both early and late stages of the disease. From our analysis, we derived a 4-protein prognostic biomarker panel that may help direct care. Given the ease of implementation, a panel of these 4 proteins or subsets thereof has the potential to be widely applied in an emergency setting in resource-limited regions.

Published
2022
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2. New Antibody-Free Mass Spectrometry-Based Quantification Reveals That C9ORF72 Long Protein Isoform Is Reduced in the Frontal Cortex of Hexanucleotide-Repeat Expansion Carriers

Author

Arthur Viodé, Clémence Fournier, Agnès Camuzat, François Fenaille, NeuroCEB Brain Bank, Morwena Latouche, Fanny Elahi, Isabelle Le Ber, Christophe Junot, Foudil Lamari, Vincent Anquetil, François Becher, Franck Letournel, Anne Vital, Françoise Chapon, Catherine Godfraind, Claude-Alain Maurage, Vincent Deramecourt, David Meyronnet, Nathalie Streichenberger, André Maues de Paula, Valérie Rigau, Fanny Vandenbos-Burel, Charles Duyckaerts, Danielle Seilhean, Véronique Sazdovitch, Serge Milin, Dan Christian Chiforeanu, Annie Laquerrière, and Béatrice Lannes

Subjects
frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), C9ORF72, TDP-43, TDP43, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease characterized by behavioral and language disorders. The main genetic cause of FTD is an intronic hexanucleotide repeat expansion (G4C2)n in the C9ORF72 gene. A loss of function of the C9ORF72 protein associated with the allele-specific reduction of C9ORF72 expression is postulated to contribute to the disease pathogenesis. To better understand the contribution of the loss of function to the disease mechanism, we need to determine precisely the level of reduction in C9ORF72 long and short isoforms in brain tissue from patients with C9ORF72 mutations. In this study, we developed a sensitive and robust mass spectrometry (MS) method for quantifying C9ORF72 isoform levels in human brain tissue without requiring antibody or affinity reagent. An optimized workflow based on surfactant-aided protein extraction and pellet digestion was established for optimal recovery of the two isoforms in brain samples. Signature peptides, common or specific to the isoforms, were targeted in brain extracts by multiplex MS through the parallel reaction monitoring mode on a Quadrupole–Orbitrap high resolution mass spectrometer. The assay was successfully validated and subsequently applied to frontal cortex brain samples from a cohort of FTD patients with C9ORF72 mutations and neurologically normal controls without mutations. We showed that the C9ORF72 short isoform in the frontal cortices is below detection threshold in all tested individuals and the C9ORF72 long isoform is significantly decreased in C9ORF72 mutation carriers.

Published
2018
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3. Common mouse models of tauopathy reflect early but not late human disease

Author

Kathrin Wenger, Arthur Viode, Christoph N. Schlaffner, Patrick van Zalm, Long Cheng, Tammy Dellovade, Xavier Langlois, Anthony Bannon, Rui Chang, Theresa R. Connors, Derek Oakley, Bernhard Renard, Juri Rappsilber, Bradley Hyman, Hanno Steen, and Judith A. Steen

Subjects
Alzheimer’s disease, Human Tau, Post-translational modifications, Protein aggregation, Tauopathy, Mouse model, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Background Mouse models that overexpress human mutant Tau (P301S and P301L) are commonly used in preclinical studies of Alzheimer’s Disease (AD) and while several drugs showed therapeutic effects in these mice, they were ineffective in humans. This leads to the question to which extent the murine models reflect human Tau pathology on the molecular level. Methods We isolated insoluble, aggregated Tau species from two common AD mouse models during different stages of disease and characterized the modification landscape of the aggregated Tau using targeted and untargeted mass spectrometry-based proteomics. The results were compared to human AD and to human patients that suffered from early onset dementia and that carry the P301L Tau mutation. Results Both mouse models accumulate insoluble Tau species during disease. The Tau aggregation is driven by progressive phosphorylation within the proline rich domain and the C-terminus of the protein. This is reflective of early disease stages of human AD and of the pathology of dementia patients carrying the P301L Tau mutation. However, Tau ubiquitination and acetylation, which are important to late-stage human AD are not represented in the mouse models. Conclusion AD mouse models that overexpress human Tau using risk mutations are a suitable tool for testing drug candidates that aim to intervene in the early formation of insoluble Tau species promoted by increased phosphorylation of Tau.

Published
2023
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4. Using plasma proteomics to investigate viral infections of the central nervous system including patients with HIV-associated neurocognitive disorders

Author

Saima Ahmed, Arthur Viode, Patrick van Zalm, Judith Steen, Shibani S. Mukerji, and Hanno Steen

Subjects
Central Nervous System, Proteomics, Cellular and Molecular Neuroscience, Proteome, Neurology, Virology, Neurocognitive Disorders, Humans, HIV Infections, Pilot Projects, Neurology (clinical), Biomarkers, Article
Abstract

State-of-the-art liquid chromatography/mass spectrometry (LC/MS)-based proteomic technologies, using microliter amounts of patient plasma, can detect and quantify several hundred plasma proteins in a high throughput fashion, allowing for the discovery of clinically relevant protein biomarkers and insights into the underlying pathobiological processes. Using such an in-house developed high throughput plasma proteomics allowed us to identify and quantify > 400 plasmas proteins in 15 minutes per samples, i.e., a throughput of 100 samples/day. We demonstrated the clinical applicability of our method in this pilot study by mapping the plasma proteomes from patients infected with human immunodeficiency virus (HIV) or herpes virus, both groups with involvement of the central nervous system (CNS). We found significant disease-specific differences in the plasma proteomes. The most notable difference was a decrease in the levels of several coagulation-associated proteins in HIV vs. herpes virus, amongst other dysregulated biological pathways providing insight into the differential pathophysiology of HIV compared to herpes virus infection. In a subsequent analysis, we found several plasma proteins associated with immunity and metabolism to differentiate patients with HIV-associated neurocognitive disorders (HAND) compared to cognitively normal people with HIV (PWH), suggesting the presence of plasma-based biomarkers to distinguishing HAND from cognitively normal PWH. Overall, our high-throughput plasma proteomics pipeline enables identification of distinct proteomic signatures of HIV and herpes virus, which may help illuminate divergent pathophysiology behind virus-associated neurological disorders.

Published
2022
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5. Common mouse models of tauopathy reflect early but not late human disease

Author

Kathrin Wenger, Arthur Viode, Christoph N. Schlaffner, Patrick van Zalm, Long Cheng, Tammy Dellovade, Xavier Langlois, Anthony Bannon, Theresa R. Connors, Derek Oakley, Bernhard Renard, Juri Rappsilber, Bradley Hyman, Hanno Steen, and Judith Steen

Abstract

Background: Mouse models that overexpress human mutant Tau (P301S and P301L) are commonly used in preclinical studies of Alzheimer’s Disease (AD) and while several drugs showed therapeutic effects in these mice, they were ineffective in humans. This leads to the question to which extent the murine models reflect human Tau pathology on the molecular level. Methods: We isolated pathological Tau species from two common AD mouse models during different stages of disease and characterized the modification landscape of the aggregated Tau using targeted and untargeted mass spectrometry-based proteomics. The results were compared to human AD and to human carriers of the P301L Tau mutation that suffered from early onset dementia. Results: Both mouse models accumulate pathological Tau species during disease. The Tau aggregation is driven by progressive phosphorylation within the proline rich domaine and the C-terminus of the protein. This is reflective of early disease stages of human AD and of the pathology of human P301L carriers. However, Tau ubiquitination and acetylation, which are important to late-stage human AD are not represented in the mouse models. Conclusion: AD mouse models that overexpress human Tau using risk mutations are a suitable tool for testing drug candidates that aim to intervene in the early formation of pathological Tau species promoted by increased phosphorylation of Tau.

Published
2022
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6. Simultaneous quantification of tau and α-synuclein in cerebrospinal fluid by high-resolution mass spectrometry for differentiation of Lewy Body Dementia from Alzheimer's Disease and controls

Author

Arthur Viode, Marc Verny, Imen Benyounes, Bruno Dubois, François Fenaille, Foudil Lamari, François Becher, Christophe Junot, Stéphane Epelbaum, Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Service de gériatrie [CHU Pitié-Salpêtrière], 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)-Médicaments et Technologies pour la Santé (MTS), 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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Médecine Gériatrique [CHU Pitié-Salpêtrière], 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Proteomics, Pathology, 02 engineering and technology, Tandem mass spectrometry, 01 natural sciences, Biochemistry, Analytical Chemistry, Cerebrospinal fluid, Tandem Mass Spectrometry, Diagnosis, Electrochemistry, Multiplex, Trypsin, Phosphorylation, Peptide sequence, Parkinsons-disease, Spectroscopy, Reveals, Serine Endopeptidases, 021001 nanoscience & nanotechnology, 3. Good health, alpha-Synuclein, Alzheimer's disease, 0210 nano-technology, Lewy Body Disease, medicine.medical_specialty, Cells, tau Proteins, Diagnosis, Differential, Alzheimer Disease, mental disorders, medicine, Environmental Chemistry, Dementia, [CHIM]Chemical Sciences, Humans, Amino Acid Sequence, Lewy body, Dementia with Lewy bodies, business.industry, Protein, 010401 analytical chemistry, Beta, medicine.disease, Peptide Fragments, 0104 chemical sciences, nervous system diseases, nervous system, Proteolysis, business, Peptides, Biomarkers, Chromatography, Liquid
Abstract

Tau and alpha-synuclein are central in several neurodegenerative diseases, including Alzheimer Disease (AD), Dementia with Lewy Bodies (DLB) and Parkinson Disease (PD). New analytical methods for precise quantification of cerebrospinal fluid (CSF) levels of both tau and alpha-synuclein are required to differentiate between dementias or monitor therapeutic responses. Notably, levels of total alpha-synuclein reported by ELISA are inconsistent among studies, impacted by antibody specificity or lack of standardization. Here, we report on the development and validation of a sensitive and robust mass spectrometry-based assay for the simultaneous quantification of tau and alpha-synuclein in CSF. The optimized workflow avoided any affinity reagents, and involved the combination of two enzymes, Glu-C and trypsin for optimal sequence coverage of alpha-synuclein acidic C-terminus. Up to 7 alpha-synuclein peptides were quantified, including the C-terminal peptide (132-140), resulting in a sequence coverage of 54% in CSF. The lower limits of quantification (LLOQ) ranged from 0.1 ng mL(-1) to 1 ng mL(-1) depending on the peptide. Regarding CSF tau, 4 peptides common to all isoforms were monitored, and LLOQ ranged from 0.5 ng mL(-1) to 0.75 ng mL(-1). The multiplex method was successfully applied to CSF samples from AD and DLB patients, two clinically overlapping neurodegenerative diseases. CSF alpha-synuclein levels were significantly lower in DLB patients compared to AD and controls. Moreover, tau and alpha-synuclein concentrations showed opposite trends in AD and DLB patients, suggesting the benefit of combining the two biomarkers for differentiation of DLB from AD and controls.

Published
2019
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7. Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease

Author

Judith A. Steen, Dinorah Jean-Gilles, Pieter Beerepoot, Naomi Klickstein, Bradley T. Hyman, Mark B. De Los Santos, Tarun V. Kamath, Renee Moore, Arthur Viode, Aurélien Lathuilière, Lori B. Chibnik, Matthew P. Frosch, Ryan C. Clark, Derek H. Oakley, Alberto Serrano-Pozo, Benjamin D. Moore, Fiona Elwood, Rudolph E. Tanzi, Diana L. Corjuc, Simon Dujardin, Analiese R. Fernandes, Matthew E. Kennedy, Patrick M. Dooley, Bianca T. Corjuc, Kristina Mullin, Caitlin Commins, and Kevin Atchison

Subjects
0301 basic medicine, Male, Cerebral Cortex / metabolism, Neurofibrillary Tangles / pathology, Disease, Protein aggregation, Severity of Illness Index, 0302 clinical medicine, Neurofibrillary Tangles / metabolism, Cognitive Dysfunction / pathology, Age of Onset, Phosphorylation, Aged, 80 and over, Cerebral Cortex, Tau Proteins / genetics, Cognition, Neurofibrillary Tangles, General Medicine, Middle Aged, Phenotype, 3. Good health, Alzheimer Disease / genetics, medicine.anatomical_structure, Cerebral Cortex / pathology, Cerebral cortex, 030220 oncology & carcinogenesis, Female, tau Proteins, Biology, Protein Aggregation, Pathological, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Genetic Heterogeneity, Alzheimer Disease, Protein Aggregation, Pathological / genetics, medicine, Humans, Cognitive Dysfunction, Aged, Protein Aggregation, Pathological / pathology, Genetic heterogeneity, Neurofibrillary Tangles / genetics, Alzheimer Disease / pathology, Cancer, medicine.disease, Alzheimer Disease / metabolism, 030104 developmental biology, Cognitive Dysfunction / genetics, Age of onset, Neuroscience
Abstract

Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline1. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity2,3. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with 'typical' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.

Published
2019

8. Author Correction: Tau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease

Author

Lori B. Chibnik, Benjamin D. Moore, Arthur Viode, Fiona Elwood, Tarun V. Kamath, Renee Moore, Patrick M. Dooley, Derek H. Oakley, Dinorah Jean-Gilles, Pieter Beerepoot, Alberto Serrano-Pozo, Diana L. Corjuc, Naomi Klickstein, Bradley T. Hyman, Kevin Atchison, Mark B. De Los Santos, Matthew P. Frosch, Aurélien Lathuilière, Judith A. Steen, Kristina Mullin, Analiese R. Fernandes, Matthew E. Kennedy, Caitlin Commins, Rudolph E. Tanzi, Simon Dujardin, Ryan C. Clark, and Bianca T. Corjuc

Subjects
0303 health sciences, media_common.quotation_subject, MEDLINE, General Medicine, Computational biology, Disease, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Clinical heterogeneity, 030304 developmental biology, Diversity (politics), media_common
Published
2021
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9. βAPP Processing Drives Gradual Tau Pathology in an Age-Dependent Amyloid Rat Model of Alzheimer’s Disease

Author

Jérôme Braudeau, Nicola Salvatore Orefice, François Becher, Charlène Joséphine, Mickael Audrain, Benoit Souchet, Alexis Haddjeri, Yvette Akwa, Alexis-Pierre Bemelmans, Sandro Alves, Nathalie Cartier, Jean-Marie Billard, Thierry Delzescaux, Arthur Viode, Patrick Dutar, Brigitte Potier, Philippe Hantraye, Satoru Tada, Romain Fol, Nicole Déglon, Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Sorbonne Paris Cité (USPC), 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), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut d'Imagerie BioMédicale (I2BM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), 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)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Centre de Psychiatrie et Neurosciences (U894)

Subjects
Male, 0301 basic medicine, Amyloid, Cognitive Neuroscience, Transgene, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Genetic Vectors, Long-Term Potentiation, Hippocampus, Plaque, Amyloid, tau Proteins, Inflammation, Disease, Protein aggregation, Protein Aggregation, Pathological, Amyloid beta-Protein Precursor, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, mental disorders, Presenilin-1, medicine, Animals, Humans, Rats, Wistar, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Amyloid beta-Peptides, business.industry, Long-term potentiation, medicine.disease, Peptide Fragments, Disease Models, Animal, 030104 developmental biology, Disease Progression, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Tauopathy, medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

The treatment of Alzheimer's disease (AD) remains challenging and requires a better in depth understanding of AD progression. Particularly, the link between amyloid protein precursor (APP) processing and Tau pathology development remains poorly understood. Growing evidences suggest that APP processing and amyloid-β (Aβ) release are upstream of Tau pathology but the lack of animal models mimicking the slow progression of human AD raised questions around this mechanism. Here, we described that an AD-like βAPP processing in adults wild-type rats, yielding to human APP, βCTF and Aβ levels similar to those observed in AD patients, is sufficient to trigger gradual Tauopathy. The Tau hyperphosphorylation begins several months before the formation of both amyloid plaques and tangle-like aggregates in aged rats and without associated inflammation. Based on a longitudinal characterization over 30 months, we showed that extrasynaptic and emotional impairments appear before long-term potentiation deficits and memory decline and so before Aβ and Tau aggregations. These compelling data allowed us to (1) experimentally confirm the causal relationship between βAPP processing and Tau pathology in vivo and without Tau transgene overexpression, (2) support the amyloidogenic cascade and (3) propose a 4-step hypothesis of prodromal AD progression.

Published
2018
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10. On-a-chip tryptic digestion of transthyretin: a step toward an integrated microfluidic system for the follow-up of familial transthyretin amyloidosis

Author

jeanne bataille, Antoine Pallandre, Jörg Peter Kutter, Arthur Viode, Stéphanie Descroix, Josiane P. Lafleur, François Becher, Isabelle Le Potier, Fanny Varenne, Myriam Taverna, Christian Poüs, Iago Pereiro, camille roesch, Claire Smadja, Université Paris Saclay (COmUE), Faculté de Pharmacie, Université Paris-Sud - Paris 11 (UP11), Institut Curie [Paris], University of Copenhagen = Københavns Universitet (KU), IZON Sciences Ldt, Partenaires INRAE, Hôpital Antoine Béclère, Assistance Publique - Hôpitaux de Paris (AP-HP), Laboratoire de Chimie Physique D'Orsay (LCPO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Nanosciences et Nanotechnologies (C2N (UMR_9001)), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), fellowship programme of DIM Analytics, and DIGIDIAG projects - French National Research Agency (ANR) as part of the Investissements d'Avenir programme [ANR 10-NANO 0207]

Subjects
0301 basic medicine, proteolysis, Hydrochloride, diagnosis, monoliths, [SDV]Life Sciences [q-bio], Peptide, protein digestion, 01 natural sciences, Biochemistry, magnetic beads, Analytical Chemistry, 03 medical and health sciences, Hydrolysis, chemistry.chemical_compound, Electrochemistry, medicine, solvent systems, Humans, Prealbumin, Environmental Chemistry, Monolith, Spectroscopy, chemistry.chemical_classification, enzyme reactors, Amyloid Neuropathies, Familial, geography, geography.geographical_feature_category, Chromatography, biology, Chemistry, 010401 analytical chemistry, high-efficiency, Reproducibility of Results, Substrate (chemistry), nutritional and metabolic diseases, Microfluidic Analytical Techniques, mass-spectrometry, Trypsin, 0104 chemical sciences, Transthyretin, trypsin, 030104 developmental biology, biology.protein, Microreactor, medicine.drug
Abstract

International audience; A microfluidic microreactor for trypsin mediated transthyretin (TTR) digestion has been developed as a step towards the elaboration of a fully integrated microdevice for the detection of a rare and disabling disease, the familial transthyretin amyloidosis (ATTR) which is related to specific TTR mutations. Therefore, an enzymatic microreactor coupled to an analytical step able to monitor the mutation of TTR on specific peptide fragments would allow an accurate monitoring of the treatment efficiency of ATTR. In this study, two types of immobilized trypsin microreactors have been investigated: a new miniaturized, microfluidic fluidized bed packed with trypsin functionalized magnetic particles (MPs), and a thiol-ene (TE) monolithbased chip. Their performances were first demonstrated with N-benzoyl-DL-arginine-4-nitroanilide hydrochloride BApNA, a low molecular weight substrate. High reaction yields (75.2%) have been reached within 0.6 min for the TE-based trypsin microreactor, while a lower yield (12.4%) was obtained for the micro-fluidized bed within a similar residence time. Transposition of the optimized conditions, developed with BApNA, to TTR digestion in the TE-based trypsin microreactor was successfully performed. We demonstrated that the TE-chip can achieve an efficient and reproducible digestion of TTR. This has been assessed by MS detection. In addition, TTR hydrolysis led to the production of a fragment of interest allowing the therapeutic follow-up of more than twenty possible ATTR mutations. High sequence coverage (90%), similar to those obtained with free trypsin, was achieved in a short time (2.4 min). Repeated experiments showed good reproducibility (RSD = 6.8%). These promising results open up the route for an innovative treatment follow-up dedicated to ATTR.

Published
2018
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