Search

Your search keyword '"Jérôme Braudeau"' showing total 26 results
Start Over Author "Jérôme Braudeau"
26 results on '"Jérôme Braudeau"'

1. Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice

Author

Benoît Souchet, Mickael Audrain, Jean Marie Billard, Julien Dairou, Romain Fol, Nicola Salvatore Orefice, Satoru Tada, Yuchen Gu, Gaelle Dufayet-Chaffaud, Emmanuelle Limanton, François Carreaux, Jean-Pierre Bazureau, Sandro Alves, Laurent Meijer, Nathalie Janel, Jérôme Braudeau, and Nathalie Cartier

Subjects
Alzheimer’s disease, DYRK1A, Proteolysis, Kinase specificity, Therapeutic approach, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Recent evidences suggest the involvement of DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1 A) in Alzheimer’s disease (AD). Here we showed that DYRK1A undergoes a proteolytic processing in AD patients hippocampus without consequences on its kinase activity. Resulting truncated forms accumulate in astrocytes and exhibit increased affinity towards STAT3ɑ, a regulator of inflammatory process. These findings were confirmed in APP/PS1 mice, an amyloid model of AD, suggesting that this DYRK1A cleavage is a consequence of the amyloid pathology. We identified in vitro the Leucettine L41 as a compound able to prevent DYRK1A proteolysis in both human and mouse protein extracts. We then showed that intraperitoneal injections of L41 in aged APP/PS1 mice inhibit STAT3ɑ phosphorylation and reduce pro-inflammatory cytokines levels (IL1- β, TNF-ɑ and IL-12) associated to an increased microglial recruitment around amyloid plaques and decreased amyloid-β plaque burden. Importantly, L41 treatment improved synaptic plasticity and rescued memory functions in APP/PS1 mice. Collectively, our results suggest that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. Further evaluation of inhibitors of DYRK1A truncation promises a new therapeutic approach for AD.

Published
2019
Full Text
View/download PDF

3. PTD–XIAP protects against cerebral ischemia by anti-apoptotic and transcriptional regulatory mechanisms

Author

Christelle Guégan, Jérôme Braudeau, Cécile Couriaud, Gunnar P.H. Dietz, Pierre Lacombe, Mathias Bähr, Marika Nosten-Bertrand, and Brigitte Onténiente

Subjects
Apoptosis, Caspase, Cell penetrating peptide, Protein transduction domain, Neuroprotection, Permanent MCAO, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Caspases play a major role in the infarction process that follows occlusion of cerebral arteries and are important targets for stroke therapy. We have generated three fusion proteins that link various domains of the X chromosome-linked inhibitor of apoptosis (XIAP), a potent caspase inhibitor, to the protein transduction domain (PTD) of HIV-1/Tat, and have tested their efficacy after distal occlusion of the middle cerebral artery (dMCAO) in mice. PTD–XIAP failed to accumulate in brain structures after intravenous (iv) delivery, but properly transduced cortical cells when applied topically. Shorter constructs efficiently targeted the lesion after iv delivery. All proteins retained their caspase inhibitory activity and significantly reduced infarct volumes. PTD–XIAP reversed long-term impairments in the water maze test. Sequential activation of transcription factors was observed, suggesting that the effects of XIAP are mediated by both direct inhibition of apoptotic mechanisms and secondary regulation of transcription factors involved in neuronal survival.

Published
2006
Full Text
View/download PDF

4. Blood‐based detection of early‐stage Alzheimer using multiomics and machine learning

Author

Benoit Souchet, Jérôme Braudeau, Alkéos Michaïl, Baptiste Billoir, Juan Fortea, Alberto Lleó, Claire Paquet, and François Mouton-Liger

Subjects
Epidemiology, business.industry, Computer science, Health Policy, Machine learning, computer.software_genre, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neurology (clinical), Artificial intelligence, Stage (hydrology), Geriatrics and Gerontology, business, computer
Published
2020
Full Text
View/download PDF

5. Transient increase in sAPPα secretion in response to Aβ1–42 oligomers: an attempt of neuronal self-defense?

Author

Lucie Gorisse-Hussonnois, Mickael Audrain, Jérôme Braudeau, Emilie Dorard, Bernadette Allinquant, Christiane Rose, and Nathalie Cartier

Subjects
Male, 0301 basic medicine, Aging, Time Factors, Amyloid, ADAM10, medicine.medical_treatment, ADAM17 Protein, Hippocampus, Neuroprotection, ADAM10 Protein, Amyloid beta-Protein Precursor, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Amyloid precursor protein, Animals, Secretion, RNA, Small Interfering, Cells, Cultured, Neurons, Amyloid beta-Peptides, Cell Death, biology, Chemistry, General Neuroscience, Growth factor, medicine.disease, Peptide Fragments, Cell biology, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Neurology (clinical), Neuron, Amyloid Precursor Protein Secretases, Geriatrics and Gerontology, Alzheimer's disease, Neuroscience, Biomarkers, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Amyloid precursor protein (APP), a key molecule of Alzheimer disease, is metabolized in 2 antagonist pathways generating the soluble APP alpha (sAPPα) having neuroprotective properties and the beta amyloid (Aβ) peptide at the origin of neurotoxic oligomers, particularly Aβ1–42. Whether extracellular Aβ1–42 oligomers modulate the formation and secretion of sAPPα is not known. We report here that the addition of Aβ1–42 oligomers to primary cortical neurons induced a transient increase in α-secretase activity and secreted sAPPα 6–9 hours later. Preventing the generation of sAPPα by using small interfering RNAs (siRNAs) for the α-secretases ADAM10 and ADAM17 or for APP led to increased Aβ1–42 oligomer–induced cell death after 24 hours. Neuronal injuries due to oxidative stress or growth factor deprivation also generated sAPPα 7 hours later. Finally, acute injection of Aβ1–42 oligomers into wild-type mouse hippocampi induced transient secretion of sAPPα 48–72 hours later. Altogether, these data suggest that neurons respond to stress by generating sAPPα for their survival. These data must be taken into account when interpreting sAPPα levels as a biomarker in neurological disorders.

Published
2018
Full Text
View/download PDF

6. 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
Full Text
View/download PDF

7. O5‐06‐04: AAV‐CYP46A1 BRAIN DELIVERY MITIGATES ALZHEIMER'S DISEASE: FROM MOUSE MODELS TO NON‐HUMAN PRIMATES

Author

Antonin Lamaziere, Mickael Audrain, Gaelle Dufayet-Chaffaud, Sandro Alves, Kristin Michaelsen-Preusse, Gaëtan Despres, Romain Fol, Françoise Fouquet, Martin Korte, Aurélie Berniard, Philippe Hantraye, Jérôme Braudeau, Emilie Rey, Nathalie Cartier, Patrick Aubourg, Romina Aron Badin, and Françoise Piguet

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Non-human, Medicine, Neurology (clinical), Disease, Geriatrics and Gerontology, business, Neuroscience
Published
2018
Full Text
View/download PDF

8. Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer’s disease mouse model

Author

Jérôme Braudeau, Mickael Audrain, Romain Fol, Alexis-Pierre Bemelmans, Ulrike Müller, Tobias Abel, Florian Brod, Susann Ludewig, Nathalie Cartier, Jan-Peter Roederer, Martin Korte, Sascha W. Weyer, and Christian J. Buchholz

Subjects
Male, 0301 basic medicine, Genetic Vectors, Morris water navigation task, Mice, Transgenic, Plaque, Amyloid, Bioinformatics, Hippocampus, Pathology and Forensic Medicine, Tissue Culture Techniques, Amyloid beta-Protein Precursor, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Atrophy, Downregulation and upregulation, Alzheimer Disease, Presenilin-1, Amyloid precursor protein, Animals, Humans, Medicine, Maze Learning, Neurons, biology, Microglia, business.industry, TREM2, Brain, Genetic Therapy, Dependovirus, medicine.disease, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Synapses, Synaptic plasticity, biology.protein, Neurology (clinical), Amyloid Precursor Protein Secretases, business, Neuroscience, 030217 neurology & neurosurgery, Neurotrophin
Abstract

Alzheimer's disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions. It is commonly assumed that these deficits arise due to β-amyloid accumulation and plaque deposition. However, increasing evidence indicates that loss of physiological APP functions mediated predominantly by neurotrophic APPsα produced in the non-amyloidogenic α-secretase pathway may contribute to AD pathogenesis. Upregulation of APPsα production via induction of α-secretase might, however, be problematic as this may also affect substrates implicated in tumorigenesis. Here, we used a gene therapy approach to directly overexpress APPsα in the brain using AAV-mediated gene transfer and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1∆E9 AD model mice. Sustained APPsα overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and partially rescued spine density deficits. Importantly, AAV-APPsα treatment also resulted in a functional rescue of spatial reference memory in the Morris water maze. Moreover, we demonstrate a significant reduction of soluble Aβ species and plaque load. In addition, APPsα induced the recruitment of microglia with a ramified morphology into the vicinity of plaques and upregulated IDE and TREM2 expression suggesting enhanced plaque clearance. Collectively, these data indicate that APPsα can mitigate synaptic and cognitive deficits, despite established pathology. Increasing APPsα may therefore be of therapeutic relevance for AD.

Published
2015
Full Text
View/download PDF

9. Reducing Gabaergic Inhibition Restores Cognitive Functions in a Mouse Model of Down Syndrome

Author

Marie-Claude Potier, Luce Dauphinot, Benoît Delatour, Jérôme Braudeau, 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 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), 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), 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)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Down syndrome, GABA Agents, [SDV]Life Sciences [q-bio], Central nervous system, Inhibitory postsynaptic potential, Mice, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Receptors, GABA, medicine, Animals, Humans, Inverse agonist, Receptor, ComputingMilieux_MISCELLANEOUS, gamma-Aminobutyric Acid, 030304 developmental biology, Pharmacology, 0303 health sciences, General Neuroscience, GABA receptor antagonist, medicine.disease, 3. Good health, Disease Models, Animal, medicine.anatomical_structure, Synaptic plasticity, Down Syndrome, Cognition Disorders, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

Alterations in excitatory-inhibitory balance occur in Down syndrome and could be responsible for cognitive deficits observed through the life of all individuals carrying an extra copy of chromosome 21. Excess of inhibition in the adult could produce synaptic plasticity deficits that may be a primary mechanism contributing to learning and memory impairments. In this study we discuss pharmacological treatments that could potentially alleviate neuronal inhibition and have been tested in a mouse model of Down syndrome. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system that binds to GABA-benzodiazepine receptors, opens a chloride channel and reduces neuronal excitability. These receptors have been extensively studied as targets for treatment of epilepsy, anxiety, sleep, cognitive disorders and the induction of sedation. Molecules that are either antagonists or inverse agonists of the GABA-benzodiazepine receptors are able to reduce inhibitory GABAergic transmission. However modulating the excitatory-inhibitory balance towards increase of cognition without inducing seizures remains difficult particularly when using GABA antagonists. In this study we review data from the literature obtained using inverse agonists selective for the α5-subunit containing receptor. Such inverse agonists, initially developed as cognitive enhancers for treatment of memory impairments, proved to be very efficient in reversing learning and memory deficits in a Down syndrome mouse model after acute treatment.

Published
2014
Full Text
View/download PDF

10. Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

Author

Baptiste Billoir, Laurent Lecanu, Satoru Tada, Jérôme Braudeau, Mickael Audrain, and Benoit Souchet

Subjects
0301 basic medicine, business.industry, Disease, Computational biology, Phase (combat), lcsh:RC346-429, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Text mining, Developmental Neuroscience, Drug development, Perspective, Medicine, business, 030217 neurology & neurosurgery, lcsh:Neurology. Diseases of the nervous system
Published
2018

11. Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer’s disease mice

Author

Romain Fol, Kristin Michaelsen-Preusse, Martin Korte, Nathalie Cartier, Jérôme Braudeau, Sandro Alves, Guillaume Churlaud, David Klatzmann, Mickael Audrain, Benoit Souchet, 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, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Zoological Institute, Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig], Helmholtz Centre for Infection Research (HZI), Université Paris-Sud - Paris 11 (UP11) - Commissariat à l'énergie atomique et aux énergies alternatives (CEA) - Institut National de la Santé et de la Recherche Médicale (INSERM), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Université Pierre et Marie Curie - Paris 6 (UPMC) - CHU Pitié-Salpêtrière [APHP], Technische Universität Braunschweig [Braunschweig], Helmholtz - Centre for Infection Research, HAL-UPMC, Gestionnaire, 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), Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany., 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)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Male, 0301 basic medicine, Pathology, Hippocampus, Morris water navigation task, Plaque, Amyloid, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, Aldesleukin, Aged, 80 and over, Neurons, Neuronal Plasticity, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Neurodegeneration, AAV, 3. Good health, Female, Alzheimer's disease, Psychology, Antipsychotic Agents, medicine.medical_specialty, Dendritic Spines, Mice, Transgenic, Presenilin, Immunomodulation, 03 medical and health sciences, Gene therapy, Alzheimer Disease, Presenilin-1, medicine, Animals, Humans, Neuroinflammation, Aged, Memory Disorders, Excitatory Postsynaptic Potentials, medicine.disease, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, Case-Control Studies, Astrocytes, Synapses, Synaptic plasticity, Interleukin-2, Neurology (clinical), Therapy, Neuroscience, 030217 neurology & neurosurgery, Immunosuppression, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Neurological diseases
Abstract

International audience; Interleukin-2 (IL-2)-deficient mice have cytoarchitectural hippocampal modifications and impaired learning and memory ability reminiscent of Alzheimer’s disease. IL-2 stimulates regulatory T cells whose role is to control inflammation. As neuroinflammation contributes to neurodegeneration, we investigated IL-2 in Alzheimer’s disease. Therefore, we investigated IL-2 levels in hippocampal biopsies of patients with Alzheimer’s disease relative to age-matched control individuals. We then treated APP/PS1ΔE9 mice having established Alzheimer’s disease with IL-2 for 5 months using single administration of an AAV-IL-2 vector. We first found decreased IL-2 levels in hippocampal biopsies of patients with Alzheimer’s disease. In mice, IL-2-induced systemic and brain regulatory T cells expansion and activation. In the hippocampus, IL-2 induced astrocytic activation and recruitment of astrocytes around amyloid plaques, decreased amyloid-β42/40 ratio and amyloid plaque load, improved synaptic plasticity and significantly rescued spine density. Of note, this tissue remodelling was associated with recovery of memory deficits, as assessed in the Morris water maze task. Altogether, our data strongly suggest that IL-2 can alleviate Alzheimer’s disease hallmarks in APP/PS1ΔE9 mice with established pathology. Therefore, this should prompt the investigation of low-dose IL-2 in Alzheimer’s disease and other neuroinflammatory/neurodegenerative disorders.

Published
2016
Full Text
View/download PDF

12. Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology

Author

Kristin Michaelsen-Preusse, Sophie Ayciriex, David Blum, Luc Buée, Marie-Claude Potier, Ivan Bièche, Francisco-Jose Fernandez-Gomez, Fathia Djelti, Luce Dauphinot, Jérôme Braudeau, Raphaëlle Caillierez, Nathalie Cartier, Marie-Anne Burlot, Olivier Laprévote, Benoit Gautier, Patrick Dutar, Martin Korte, Mickael Audrain, Brigitte Potier, Nicolas Auzeil, Jennifer Varin, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, 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, Zoological Institute, Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig], Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Inserm U986, Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes adaptatifs : des organismes aux communautés, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Alzheimer & Tauopathies [JPArc], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Facultés des sciences pharmaceutiques et biologiques, Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463), 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), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Max Planck Institute for Cell Biology and Genetics, Max-Planck-Institut, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), Thérapie génique, Génomique et Epigénomique ( U 1169 ), 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 ), Technische Universität Braunschweig [Braunschweig], Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux ( EA 7331 ), Institut National de la Santé et de la Recherche Médicale, Mécanismes adaptatifs : des organismes aux communautés ( MECADEV ), Muséum National d'Histoire Naturelle ( MNHN ) -Centre National de la Recherche Scientifique ( CNRS ), Alzheimer & Tauopathies ( Equipe 1 ), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172 ( JPArc ), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Institut de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire ( EA 4463 ), 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 ), Department of Cellular and Systems Neurobiology, Max-Planck-Institut für Neurobiologie, Service MIRCEN ( MIRCEN ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Alzheimer & Tauopathies (Equipe 1), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, 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 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, 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), and Université Paris-Saclay-Institut de Biologie François JACOB (JACOB)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Mice, chemistry.chemical_compound, 0302 clinical medicine, Cerebrospinal fluid, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Gliosis, Phosphorylation, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], General Medicine, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, medicine.anatomical_structure, Tauopathies, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Alzheimer's disease, medicine.symptom, medicine.medical_specialty, Amyloid, Central nervous system, Mice, Transgenic, tau Proteins, Biology, 03 medical and health sciences, Alzheimer Disease, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cholesterol 24-Hydroxylase, Genetics, medicine, Animals, Humans, Cholesterol 24-hydroxylase, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, 030304 developmental biology, Memory Disorders, Cholesterol, medicine.disease, Hydroxycholesterols, Disease Models, Animal, Endocrinology, chemistry, Steroid Hydroxylases, [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry, 030217 neurology & neurosurgery, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract

Alzheimer's disease (AD) is characterized by both amyloid and Tau pathologies. The amyloid component and altered cholesterol metabolism are closely linked, but the relationship between Tau pathology and cholesterol is currently unclear. Brain cholesterol is synthesized in situ and cannot cross the blood-brain barrier: to be exported from the central nervous system into the blood circuit, excess cholesterol must be converted to 24S-hydroxycholesterol by the cholesterol 24-hydroxylase encoded by the CYP46A1 gene. In AD patients, the concentration of 24S-hydroxycholesterol in the plasma and the cerebrospinal fluid are lower than in healthy controls. The THY-Tau22 mouse is a model of AD-like Tau pathology without amyloid pathology. We used this model to investigate the potential association between Tau pathology and CYP46A1 modulation. The amounts of CYP46A1 and 24S-hydroxycholesterol in the hippocampus were lower in THY-Tau22 than control mice. We used an adeno-associated virus (AAV) gene transfer strategy to increase CYP46A1 expression in order to investigate the consequences on THY-Tau22 mouse phenotype. Injection of the AAV-CYP46A1 vector into the hippocampus of THY-Tau22 mice led to CYP46A1 and 24S-hydroxycholesterol content normalization. The cognitive deficits, impaired long-term depression and spine defects that characterize the THY-Tau22 model were completely rescued, whereas Tau hyperphosphorylation and associated gliosis were unaffected. These results argue for a causal link between CYP46A1 protein content and memory impairments that result from Tau pathology. Therefore, CYP46A1 may be a relevant therapeutic target for Tauopathies and especially for AD.

Published
2015
Full Text
View/download PDF

13. CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease

Author

Dominique Langui, Michel Vidaud, Eloise Hudry, Nathalie Cartier, Ivan Bièche, Marc Dhenain, Sandro Alves, Olivier Laprévote, Patrick Aubourg, Sophie Ayciriex, Charles Duyckaerts, Jérôme Braudeau, Catherine Marquer, Nicolas Auzeil, Farah Chali, Marie-Claude Potier, Richard B. Miles, Fathia Djelti, Jennifer Varin, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Mécanismes adaptatifs : des organismes aux communautés, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), 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 des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Facultés des sciences pharmaceutiques et biologiques, 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), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463), 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 de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], 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), Inserm U986, Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), 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), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Max Planck Institute for Cell Biology and Genetics, Max-Planck-Institut, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), Mécanismes adaptatifs : des organismes aux communautés ( MECADEV ), Muséum National d'Histoire Naturelle ( MNHN ) -Centre National de la Recherche Scientifique ( CNRS ), Thérapie génique, Génomique et Epigénomique ( U 1169 ), 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 ), Laboratoire des Maladies Neurodégénératives - UMR 9199 ( LMN ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux ( EA 7331 ), 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 ), Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire ( EA 4463 ), 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 de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale, Service MIRCEN ( MIRCEN ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-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), 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 Paris Descartes - Paris 5 (UPD5)-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)-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 National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Hippocampal formation, Small hairpin RNA, chemistry.chemical_compound, Amyloid beta-Protein Precursor, 0302 clinical medicine, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], RNA interference, Homeostasis, Enzyme Inhibitors, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Lipid raft, ComputingMilieux_MISCELLANEOUS, Neurons, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Neurodegeneration, Brain, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Cholesterol, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Female, medicine.medical_specialty, Mice, Transgenic, Biology, 03 medical and health sciences, Alzheimer Disease, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Cholesterol 24-Hydroxylase, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Liver X receptor, 030304 developmental biology, Amyloid beta-Peptides, medicine.disease, Mice, Inbred C57BL, Endocrinology, chemistry, Steroid Hydroxylases, [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract

Abnormalities in neuronal cholesterol homeostasis have been suspected or observed in several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has not been demonstrated whether an increased abundance of cholesterol in neurons in vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology to inhibit the expression of cholesterol 24-hydroxylase, encoded by the Cyp46a1 gene, in the hippocampus of normal mice. Cholesterol 24-hydroxylase controls cholesterol efflux from the brain and thereby plays a major role in regulating brain cholesterol homeostasis. We used an adeno-associated virus vector encoding short hairpin RNA directed against the mouse Cyp46a1 mRNA to decrease the expression of the Cyp46a1 gene in hippocampal neurons of normal mice. This increased the cholesterol concentration in neurons, followed by cognitive deficits and hippocampal atrophy due to apoptotic neuronal death. Prior to neuronal death, the recruitment of the amyloid protein precursor to lipid rafts was enhanced leading to the production of β-C-terminal fragment and amyloid-β peptides. Abnormal phosphorylation of tau and endoplasmic reticulum stress were also observed. In the APP23 mouse model of Alzheimer's disease, the abundance of amyloid-β peptides increased following inhibition of Cyp46a1 expression, and neuronal death was more widespread than in normal mice. Altogether, these results suggest that increased amounts of neuronal cholesterol within the brain may contribute to inducing and/or aggravating Alzheimer's disease.

Published
2015
Full Text
View/download PDF

14. P1‐037: Gene transfer of both app and ps1 induces hippocampal impairments close to human early phases of Alzheimer's disease

Author

Mickael Audrain, Sandro Alves, Romain Fol, Nathalie Cartier, Marie-Anne Burlot, Gaelle Dufayet-Chaffaud, Nicole Déglon, Philippe Hantraye, Jérôme Braudeau, Julien Flament, Julien Valette, Jean-Marie Billard, Patrick Dutar, Brigitte Potier, and Alexis-Pierre Bemelmans

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Gene transfer, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology, Hippocampal formation, Neuroscience
Published
2015
Full Text
View/download PDF

15. P1‐027: Improved amyloid pathology contrasting with unexpected memory defects following astrocytic ApoE‐e2 overexpression in hippocampus of Alzheimer's mice

Author

Jérôme Braudeau, Alexis-Pierre Bemelmans, Bradley T. Hyman, Nathalie Cartier, Marie-Anne Burlot, Eloise Hudry, Mickael Audrain, Romain Fol, and Gaelle Dufayet-Chaffaud

Subjects
Apolipoprotein E, Amyloid pathology, Memory defects, Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Hippocampus, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience
Published
2015
Full Text
View/download PDF

16. P3‐317: Hippocampal CYP46A1 overexpression is beneficial in rodent models of Alzheimer's disease

Author

Jérôme Braudeau, Mickael Audrain, Françoise Fouquet, Patrick Aubourg, Nathalie Cartier, Sandro Alves, and Antonin Lamaziere

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Rodent, biology, Epidemiology, Health Policy, biology.animal, Neurology (clinical), Disease, Geriatrics and Gerontology, Hippocampal formation, Neuroscience
Published
2015
Full Text
View/download PDF

17. O3‐14‐03: CHOLESTEROL AND TAU PATHOLOGY: CONSEQUENCES OF AAV‐MEDIATED CHOLESTEROL‐24‐HYDROXYLASE OVEREXPRESSION IN THE THY‐TAU22 MOUSE

Author

Olivier Laprévote, Jérôme Braudeau, Nathalie Cartier, Marie-Anne Burlot, Patrick Aubourg, Laurent Pradier, Raphaëlle Caillierez, Benoit Gautier, Zommer Nadege, David Blum, Sophie Ayciriex, Jennifer Varin, Ivan Bièche, Fathia Djelti, Nicolas Auzeil, L Dauphinot, Marie-Claude Potier, and Luc Buée

Subjects
medicine.medical_specialty, Tau pathology, Epidemiology, business.industry, Cholesterol, Health Policy, Psychiatry and Mental health, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Endocrinology, Developmental Neuroscience, chemistry, Internal medicine, medicine, Neurology (clinical), Geriatrics and Gerontology, Cholesterol 24-hydroxylase, business
Published
2014
Full Text
View/download PDF

18. P1‐031: AMYLOID CASCADE INDUCTION IN AN AAV‐BASED MOUSE MODEL OF ALZHEIMER'S DISEASE

Author

Nathalie Cartier, Jérôme Braudeau, Alexis-Pierre Bemelmans, Nicole Déglon, Romain Fol, Philippe Hantraye, and Mickael Audrain

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Cancer research, Medicine, Neurology (clinical), Disease, Geriatrics and Gerontology, Amyloid cascade, business
Published
2014
Full Text
View/download PDF

19. P1‐025: CONSEQUENCES OF APOE2 OVEREXPRESSION IN ASTROCYTES IN AN ALZHEIMER'S DISEASE MOUSE MODEL

Author

Alexis-Pierre Bemelmans, Bradley T. Hyman, Mickael Audrain, Romain Fol, Gaelle Dufayet-Chaffaud, Jérôme Braudeau, Nathalie Cartier, Marie-Anne Burlot, and Eloise Hudry

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Cancer research, Medicine, Neurology (clinical), Disease, Geriatrics and Gerontology, business
Published
2014
Full Text
View/download PDF

20. Chronic Treatment with a Promnesiant GABA-A 𝜶 𝟓 -Selective Inverse Agonist Increases Immediate Early Genes Expression during Memory Processing in Mice and Rectifies Their Expression Levels in a Down Syndrome Mouse Model

Author

Jérôme Braudeau, A. Loistron, Yann Herault, Arnaud Duchon, Marie-Claude Potier, Luce Dauphinot, Robert H. Dodd, and Benoît Delatour

Subjects
Article Subject, animal diseases, Morris water navigation task, Hippocampus, Stimulation, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Inverse agonist, Medicine, Pharmacology (medical), General Pharmacology, Toxicology and Pharmaceutics, Receptor, 030304 developmental biology, 0303 health sciences, Arc (protein), business.industry, lcsh:RM1-950, α5IA, 3. Good health, lcsh:Therapeutics. Pharmacology, Molecular Medicine, Memory consolidation, business, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract

Decrease of GABAergic transmission has been proposed to improve memory functions. Indeed, inverse agonists selective forα5 GABA-A-benzodiazepine receptors (α5IA) have promnesiant activity. Interestingly, we have recently shown thatα5IA can rescue cognitive deficits in Ts65Dn mice, a Down syndrome mouse model with altered GABAergic transmission. Here, we studied the impact of chronic treatment withα5IA on gene expression in the hippocampus of Ts65Dn and control euploid mice after being trained in the Morris water maze task. In euploid mice, chronic treatment withα5IA increased IEGs expression, particularly ofc-FosandArcgenes. In Ts65Dn mice, deficits of IEGs activation were completely rescued after treatment withα5IA. In addition, normalization ofSod1overexpression in Ts65Dn mice afterα5IA treatment was observed. IEG expression regulation afterα5IA treatment following behavioral stimulation could be a contributing factor for both the general promnesiant activity ofα5IA and its rescuing effect in Ts65Dn mice alongside signaling cascades that are critical for memory consolidation and cognition.

Published
2011
Full Text
View/download PDF

21. PTD-XIAP protects against cerebral ischemia by anti-apoptotic and transcriptional regulatory mechanisms

Author

Brigitte Onténiente, Jérôme Braudeau, Marika Nosten-Bertrand, Cécile Couriaud, Gunnar P.H. Dietz, Pierre Lacombe, Mathias Bähr, and Christelle Guégan

Subjects
Male, Transcriptional Activation, Recombinant Fusion Proteins, Cerebral arteries, Protein transduction domain, Apoptosis, X-Linked Inhibitor of Apoptosis Protein, Pharmacology, Inhibitor of apoptosis, Neuroprotection, lcsh:RC321-571, Brain Ischemia, Mice, Animals, Regulatory Elements, Transcriptional, Maze Learning, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Transcription factor, Caspase, Infusion Pumps, Cerebral Cortex, Cell penetrating peptide, biology, Infarction, Middle Cerebral Artery, Cerebral Infarction, Fusion protein, Molecular biology, XIAP, Protein Structure, Tertiary, Mice, Inbred C57BL, Disease Models, Animal, Neurology, Gene Products, tat, biology.protein, Permanent MCAO
Abstract

Caspases play a major role in the infarction process that follows occlusion of cerebral arteries and are important targets for stroke therapy. We have generated three fusion proteins that link various domains of the X chromosome-linked inhibitor of apoptosis (XIAP), a potent caspase inhibitor, to the protein transduction domain (PTD) of HIV-1/Tat, and have tested their efficacy after distal occlusion of the middle cerebral artery (dMCAO) in mice. PTD–XIAP failed to accumulate in brain structures after intravenous (iv) delivery, but properly transduced cortical cells when applied topically. Shorter constructs efficiently targeted the lesion after iv delivery. All proteins retained their caspase inhibitory activity and significantly reduced infarct volumes. PTD–XIAP reversed long-term impairments in the water maze test. Sequential activation of transcription factors was observed, suggesting that the effects of XIAP are mediated by both direct inhibition of apoptotic mechanisms and secondary regulation of transcription factors involved in neuronal survival.

Published
2005

22. Activation of proinflammatory caspases by cathepsin B in focal cerebral ischemia

Author

Cécile Couriaud, Alexandra Benchoua, Aurélia Reis, Brigitte Onteniente, and Jérôme Braudeau

Subjects
0301 basic medicine, Male, Pathology, medicine.medical_specialty, Programmed cell death, Cytoplasm, Time Factors, Cerebral arteries, Ischemia, Cathepsin B, Proinflammatory cytokine, Brain Ischemia, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Animals, Caspase, Cathepsin, Inflammation, Neurons, biology, Caspase 1, medicine.disease, Immunohistochemistry, Caspases, Initiator, Cell biology, Enzyme Activation, Mice, Inbred C57BL, 030104 developmental biology, Neurology, Apoptosis, Caspases, biology.protein, Neurology (clinical), Cardiology and Cardiovascular Medicine, 030217 neurology & neurosurgery
Abstract

Cathepsins and caspases are two families of proteases that play pivotal roles in ischemic cell death. This study investigated the existence of a cross-talk between cathepsin B and proinflammatory caspases in stroke-induced cell death, as recently suggested by in vitro data. Cortical ischemic damage was induced in mice by distal and permanent occlusion of the middle cerebral artery. Cytoplasmic activation of cathepsin B was observed from the early stages of infarction, and displayed an activation pattern parallel to the activation pattern of caspase-1 and −11. Immunohistochemistry revealed the colocalization of cathepsin B with each caspase in cells of the infarct core. The apical position of cathepsin B in both caspase-activation cascades was confirmed by pretreatment of the animals with the cathepsin B inhibitor CA-074, which also potently protected cortical structures from ischemic damage, indicating involvement of the proteases in the lesion process. The results show that cathepsin B release is an early event following occlusion of cerebral arteries, which eventually triggers the activation of proinflammatory caspases in the absence of reperfusion. This new pathway may play a critical role in brain infarction by promoting inflammatory responses, and/or by amplifying the apoptotic process.

Published
2004

23. The mechanisms of cell death in focal cerebral ischemia highlight neuroprotective perspectives by anti-caspase therapy

Author

Jérôme Braudeau, Alexandra Benchoua, Christelle Guégan, Cécile Couriaud, and Brigitte Onténiente

Subjects
Programmed cell death, Pathology, medicine.medical_specialty, Necrosis, Ischemia, Apoptosis, Biochemistry, Neuroprotection, Brain Ischemia, medicine, Humans, Enzyme Inhibitors, Caspase, Pharmacology, biology, business.industry, Penumbra, medicine.disease, Fusion protein, Caspase Inhibitors, Cell biology, Stroke, biology.protein, medicine.symptom, business
Abstract

A number of studies have validated the importance of caspase activation in ischemia-induced brain damage. Caspases participate in both the initiation and execution phases of apoptosis, and play a central role in neuronal death after global cerebral ischemia. In focal ischemia, apoptosis occurs in the penumbra during the secondary phase of expansion of the lesion. However, ultrastructural and biochemical analysis have also shown signs of apoptosis in the initial lesion, or infarct core, which is traditionally considered necrotic. Specific caspase pathways are activated in the core and in the penumbra, and participate in both cytoplasmic and nuclear apoptotic events, notwithstanding their initial classification as activator or initiator caspases. This confirms previous suggestions that caspase inhibition holds tremendous neuroprotective potential in stroke and other apoptosis-related degenerative diseases. Consequently, two new approaches, aimed at treating stroke-induced brain damage by anti-apoptotic molecules, are being developed in academic and industrial laboratories. These are based, respectively, on the use of small peptide sequences corresponding to the preferred cleavage site of a caspase, and on genomic constructions derived from the fusion of endogenous anti-caspase molecules with a protein transduction domain from the human immunodeficiency virus-1. Fusion proteins containing endogenous caspases inhibitors efficiently counteract apoptosis in vitro. In in vivo models of focal cerebral ischemia, fusion proteins successfully cross the blood brain barrier and protect cells from ischemic death. This new approach by protein therapy could prove to be an interesting alternative for the reduction of the dramatic consequences of stroke, provided that the long-term efficiency of this protection in terms of functional recovery is demonstrated.

Published
2003

24. Multiomics Blood-Based Biomarkers Predict Alzheimer's Predementia with High Specificity in a Multicentric Cohort Study.

Author

Souchet B, Michaïl A, Heuillet M, Dupuy-Gayral A, Haudebourg E, Pech C, Berthemy AA, Autelitano F, Billoir B, Domoto-Reilly K, Fowler C, Grabowski T, Jayadev S, Masters CL, and Braudeau J

Subjects
Humans, Male, Female, Aged, Retrospective Studies, Sensitivity and Specificity, Animals, Cohort Studies, Prodromal Symptoms, Multiomics, Alzheimer Disease diagnosis, Alzheimer Disease blood, Biomarkers blood, Cognitive Dysfunction diagnosis, Cognitive Dysfunction blood
Abstract

Background: The primary criteria for diagnosing mild cognitive impairment (MCI) due to Alzheimer's Disease (AD) or probable mild AD dementia rely partly on cognitive assessments and the presence of amyloid plaques. Although these criteria exhibit high sensitivity in predicting AD among cognitively impaired patients, their specificity remains limited. Notably, up to 25% of non-demented patients with amyloid plaques may be misdiagnosed with MCI due to AD, when in fact they suffer from a different brain disorder. The introduction of anti-amyloid antibodies complicates this scenario. Physicians must prioritize which amyloid-positive MCI patients receive these treatments, as not all are suitable candidates. Specifically, those with non-AD amyloid pathologies are not primary targets for amyloid-modifying therapies. Consequently, there is an escalating medical necessity for highly specific blood biomarkers that can accurately detect pre-dementia AD, thus optimizing amyloid antibody prescription., Objectives: The objective of this study was to evaluate a predictive model based on peripheral biomarkers to identify MCI and mild dementia patients who will develop AD dementia symptoms in cognitively impaired population with high specificity., Design: Peripheral biomarkers were identified in a gene transfer-based animal model of AD and then validated during a retrospective multi-center clinical study., Setting: Participants from 7 retrospective cohorts (US, EU and Australia)., Participants: This study followed 345 cognitively impaired individuals over up to 13 years, including 193 with MCI and 152 with mild dementia, starting from their initial visits. The final diagnoses, established during their last assessments, classified 249 participants as AD patients and 96 as having non-AD brain disorders, based on the specific diagnostic criteria for each disorder subtype. Amyloid status, assessed at baseline, was available for 82.9% of the participants, with 61.9% testing positive for amyloid. Both amyloid-positive and negative individuals were represented in each clinical group. Some of the AD patients had co-morbidities such as metabolic disorders, chronic diseases, or cardiovascular pathologies., Measurements: We developed targeted mass spectrometry assays for 81 blood-based biomarkers, encompassing 45 proteins and 36 metabolites previously identified in AAV-AD rats., Methods: We analyzed blood samples from study participants for the 81 biomarkers. The B-HEALED test, a machine learning-based diagnostic tool, was developed to differentiate AD patients, including 123 with Prodromal AD and 126 with mild AD dementia, from 96 individuals with non-AD brain disorders. The model was trained using 70% of the data, selecting relevant biomarkers, calibrating the algorithm, and establishing cutoff values. The remaining 30% served as an external test dataset for blind validation of the predictive accuracy., Results: Integrating a combination of 19 blood biomarkers and participant age, the B-HEALED model successfully distinguished participants that will develop AD dementia symptoms (82 with Prodromal AD and 83 with AD dementia) from non-AD subjects (71 individuals) with a specificity of 93.0% and sensitivity of 65.4% (AUROC=81.9%, p<0.001) during internal validation. When the amyloid status (derived from CSF or PET scans) and the B-HEALED model were applied in association, with individuals being categorized as AD if they tested positive in both tests, we achieved 100% specificity and 52.8% sensitivity. This performance was consistent in blind external validation, underscoring the model's reliability on independent datasets., Conclusions: The B-HEALED test, utilizing multiomics blood-based biomarkers, demonstrates high predictive specificity in identifying AD patients within the cognitively impaired population, minimizing false positives. When used alongside amyloid screening, it effectively identifies a nearly pure prodromal AD cohort. These results bear significant implications for refining clinical trial inclusion criteria, facilitating drug development and validation, and accurately identifying patients who will benefit the most from disease-modifying AD treatments., Competing Interests: B.S., A.M., B.B. and J.B. are employees of the company AgenT.

Published
2024
Full Text
View/download PDF

25. Cerebral Phospho-Tau Acts Synergistically with Soluble Aβ42 Leading to Mild Cognitive Impairment in AAV-AD Rats.

Author

Souchet B, Audrain M, Gu Y, Lindberg MF, Orefice NS, Rey E, Cartier N, Janel N, Meijer L, and Braudeau J

Subjects
Amyloid beta-Peptides, Animals, Humans, Peptide Fragments, Prodromal Symptoms, Rats, tau Proteins metabolism, Alzheimer Disease diagnosis, Cognitive Dysfunction psychology
Abstract

Background: Alzheimer's disease (AD) is a continuum of events beginning with an increase in brain soluble Aβ42 followed by the appearance of hyperphosphorylated tau (P-tau, asymptomatic stage). Mild Cognitive Impairment (MCI) then appears (prodromal stage). However, the individual contribution of these two soluble proteins in the onset of the first cognitive symptoms remains unclear., Objectives: We sought to understand the specific impact of p-tau on the development of MCI in the AAV-AD rat model, a model of late-onset Alzheimer's disease (LOAD) predementia., Methods: We specifically reduced the phosphorylation level of tau while leaving Aβ42 levels unchanged using a DYRK1A protein kinase inhibitor, Leucettine L41, in an adeno-associated virus-based Alzheimer's disease (AAV-AD) rat model. Leucettine L41 was administered by intraperitoneal injection at 20 mg/kg per day in AAV-AD rats from 9 (late asymptomatic phase) to 10 (prodromal phase) months of age., Results: Decreased soluble forms of P-tau induced by chronic administration of Leucettine L41 did not change soluble Aβ42 levels but prevented MCI onset in 10-month-old AAV-AD rats., Conclusions: The present study argues that P-tau is required to induce the development of MCI. Consistent with our previous findings that soluble Aβ42 is also required for MCI onset, the data obtained in the AAV-AD rat model confirm that the transition from the asymptomatic to the prodromal stage may be caused by the combined presence of both soluble brain forms of Aβ42 and p-tau, suggesting that the development of MCI may be the consequence of their synergistic action., Competing Interests: J.B. is co-founder of AgenT SAS. J.B. and B.S. are employees of AgenT SAS. L.M. is an inventor on the Leucettine patent.

Published
2022
Full Text
View/download PDF

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

Author

Souchet B, Audrain M, Alves S, Fol R, Tada S, Orefice NS, Potier B, Dutar P, Billard JM, Cartier N, and Braudeau J

Subjects
Animals, Humans, Memantine therapeutic use, Rats, Alzheimer Disease drug therapy, Alzheimer Disease pathology, Tauopathies
Abstract

Background: Though our understanding of Alzheimer's disease (AD) remains elusive, it is well known that the disease starts long before the first signs of dementia. This is supported by the large number of symptomatic drug failures in clinical trials and the increased trend to enroll patients at predementia stages with either mild or no cognitive symptoms. However, the design of pre-clinical studies does not follow this attitude, in particular regarding the choice of animal models, often irrelevant to mimic predementia Late Onset Alzheimer's Disease (LOAD)., Objectives: We aimed to pharmacologically validate the AAV-AD rat model to evaluate preventive treatment of AD., Methods: We evaluated an N-methyl-D-aspartate receptor antagonist, named memantine, in AAV-AD rats, an age-dependent amyloid rat model which closely mimics Alzheimer's pathology including asymptomatic and prodromal stages. Memantine was used at a clinically relevant dose (20 mg daily oral administration) from 4 (asymptomatic phase) to 10 (mild cognitive impairment phase) months of age., Results: A 6-month treatment with memantine promoted a non-amyloidogenic cleavage of APP followed by a decrease in soluble Aβ42. Consequently, both long-term potentiation and cognitive impairments were prevented. By contrast, the levels of hyperphosphorylated endogenous tau remained unchanged, indicating that a long-term memantine treatment is ineffective to restrain the APP processing-induced tauopathy., Conclusions: Together, our data confirm that relevant models to LOAD, such as the AAV-AD rat, can provide a framework for a better understanding of the disease and accurate assessment of preventive treatments., Competing Interests: J.B. is co-founder of AgenT SAS. J.B. and B.S. are employees of AgenT SAS.

Published
2022
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results