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36 results on '"MESH: tau Proteins"'

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

Author

Martine Guillermier, Carole Escartin, Océane Guillemaud, Alexis-Pierre Bemelmans, Charlène Joséphine, Gilles Bonvento, Emmanuel Brouillet, Kelly Ceyzériat, Thomas Saint-Georges, Philippe Hantraye, Maria-Angeles Carrillo-de Sauvage, Karine Cambon, Sueva Bernier, Fanny Petit, Lucile Ben Haim, Anne-Sophie Hérard, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), ANR-16-TERC-0016,DecodAstro,Decoder la complexité de la réactivité astrocytaire dans les maladies neurodégénératives(2016), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, 0301 basic medicine, Aging, MESH: Hippocampus, JAK-STAT3 pathway, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Hippocampal formation, MESH: Janus Kinase 2, 0302 clinical medicine, Neuroinflammation, MESH: Animals, SOCS3, Phosphorylation, 0303 health sciences, Chemistry, General Neuroscience, MESH: STAT3 Transcription Factor, MESH: tau Proteins, 3. Good health, medicine.anatomical_structure, Alzheimer disease, Alzheimer's disease, Signal Transduction, Astrocyte, STAT3 Transcription Factor, Genetically modified mouse, Elevated plus maze, Amyloid, MESH: Mice, Transgenic, Amyloidogenic Proteins, Mice, Transgenic, tau Proteins, Viral vector, 03 medical and health sciences, medicine, Animals, 030304 developmental biology, MESH: Amyloidogenic Proteins, MESH: Phosphorylation, Activator (genetics), Janus Kinase 2, medicine.disease, MESH: Astrocytes, Disease Models, Animal, 030104 developmental biology, Astrocytes, Reactive astrocytes, Neurology (clinical), Tau, MESH: Disease Models, Animal, Geriatrics and Gerontology, Neuroscience, MESH: Alzheimer Disease, 030217 neurology & neurosurgery, Developmental Biology
Abstract

In Alzheimer disease (AD), astrocytes undergo complex changes and become reactive. The consequences of this reaction are still unclear. To evaluate the net impact of reactive astrocytes in AD, we recently developed viral vectors targeting astrocytes that either activate or inhibit the JAK2-STAT3 pathway, a central cascade controlling astrocyte reaction.We aimed to evaluate whether reactive astrocytes contribute to Tau as well as amyloid pathologies in the hippocampus of 3xTg-AD mice, an AD model that develops Tau hyperphosphorylation and aggregation in addition to amyloid deposition. JAK2-STAT3 pathway-mediated modulation of reactive astrocytes in the hippocampus of 3xTg-AD mice, did not significantly influence Tau phosphorylation or amyloid processing and deposition, at early, advanced and terminal stage of the disease. Interestingly, inhibition of the JAK2-STAT3 pathway in hippocampal astrocytes did not improve short-term spatial memory in the Y maze but it reduced anxiety in the elevated plus maze. Our unique approach to specifically manipulate reactive astrocytes in situ show these cells may impact behavioral outcomes without influencing Tau or amyloid pathology.

Published
2020

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

Author

Kaj Blennow, Sylvain Lehmann, Nicholas J. Ashton, Jordi Pegueroles, Rafael Blesa, Maria Florencia Iulita, Alberto Lleó, Miren Altuna, Valle Camacho, Henrik Zetterberg, Maria Carmona-Iragui, Daniel Alcolea, Diana Garzón, Susana Fernández, Juan Lantero-Rodriguez, Santiago Medrano-Martorell, Juan Fortea, Jordi Clarimón, Thomas K. Karikari, Olivia Belbin, Alexandre Bejanin, Laura Videla, Sílvia Valldeneu, Bessy Benejam, Isabel Barroeta, Victor Montal, Hospital de la Santa Creu i Sant Pau, Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Universitat Autònoma de Barcelona (UAB), Sahlgrenska Academy at University of Gothenburg [Göteborg], Sahlgrenska University Hospital [Gothenburg], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), Institute of Neurology [London], Fundació Catalana de Síndrome de Down [Barcelona], University of Gothenburg (GU), King‘s College London, IMIM-Hospital del Mar, Generalitat de Catalunya, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Herrada, Anthony

Subjects
Male, 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Physics and Astronomy, MESH: Cognition, Disease, Gastroenterology, Cognition, 0302 clinical medicine, Neurofilament Proteins, Medicine, Phosphorylation, MESH: Neurofilament Proteins, Cerebral Cortex, education.field_of_study, MESH: Middle Aged, Multidisciplinary, Area under the curve, Middle Aged, Alzheimer's disease, MESH: Amyloid beta-Peptides, MESH: tau Proteins, Area Under Curve, Disease Progression, Biomarker (medicine), MESH: Disease Progression, Female, medicine.symptom, Adult, medicine.medical_specialty, Down syndrome, Science, Population, tau Proteins, MESH: Atrophy, Predictive markers, Asymptomatic, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Cross-Sectional Studies, Atrophy, Alzheimer Disease, Internal medicine, Humans, Dementia, education, MESH: Humans, Amyloid beta-Peptides, MESH: Phosphorylation, business.industry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Adult, MESH: Down Syndrome, General Chemistry, medicine.disease, MESH: Cerebral Cortex, MESH: Male, Cross-Sectional Studies, 030104 developmental biology, MESH: Biomarkers, MESH: Area Under Curve, Down Syndrome, business, MESH: Female, MESH: Alzheimer Disease, Biomarkers, 030217 neurology & neurosurgery
Abstract

Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73–0.87] and 0.92 [95% CI 0.89–0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS., Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology. Here, the authors investigated whether plasma ptau181 could be a potential biomarker of AD in individuals with Down syndrome (DS) and find plasma p-tau181 can detect AD in DS adults.

Published
2021

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

Author

Yves Dauvilliers, Salvy-Córdoba, Nathalie, Michel A. Steiner, Masashi Yanagisawa, Martine Clozel, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Sleep Wake Disorders, MESH: Orexins, MESH: Glymphatic System, Translational research, tau Proteins, Disease, Pathogenesis, MESH: Tau Proteins, Alzheimer Disease, MESH: Narcolepsy, Medicine, Animals, Humans, MESH: Animals, Circadian rhythm, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive decline, Narcolepsy, Orexins, Amyloid beta-Peptides, MESH: Humans, business.industry, Sleep in non-human animals, MESH: Amyloid beta-Peptides, MESH: Sleep Wake Disorders, Biomarker (medicine), Wakefulness, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, Neuroscience, Glymphatic System, MESH: Alzheimer Disease
Abstract

International audience; Advances in translational research provide key opportunities to explore the physiological and pathological effects of sleep in different neurodegenerative diseases. Recent findings suggest that sleep-wakefulness dysfunctions may predispose to neurodegenerative disorders such as Alzheimer's disease (AD), and vice versa. New theories on the link between sleep and β-amyloid and tau secretion, accumulation and clearance, and its interaction with hypocretins/orexins (key neuropeptides regulating wakefulness) suggest mechanistic ways to better understand the impact of sleep alterations in the pathogenesis of AD. Further studies should validate whether changes in circadian rhythm and sleep-wakefulness patterns could be used for early AD diagnosis and as prognostic markers for cognitive decline. Longitudinal studies are needed, not only to validate these biomarker interactions and to determine the cause-effect relationship and the role of sleep-wakefulness behavior in the regulation of amyloid plaque and neurofibrillary tangle formation, but also to identify the best sleep therapies and related preventive strategies for AD.

Published
2021

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

Author

Baldacci, F., Lista, S., Manca, M. L., Chiesa, P. A., Cavedo, E., Lemercier, P., Zetterberg, H., Blennow, K., Habert, M. -O., Potier, M. C., Dubois, B., Vergallo, A., Hampel, H., Bakardjian, H., Benali, H., Bertin, H., Bonheur, J., Boukadida, L., Boukerrou, N., Chiesa, P., Colliot, O., Dubois, M., Epelbaum, S., Gagliardi, G., Genthon, R., Houot, M., Kas, A., Lamari, F., Levy, M., Metzinger, C., Mochel, F., Nyasse, F., Poisson, C., Potier, M. -C., Revillon, M., Santos, A., Andrade, K. S., Sole, M., Surtee, M., de Schotten, M. T., Younsi, N., Afshar, M., Aguilar, L. F., Akman-Anderson, L., Arenas, J., Avila, J., Babiloni, C., Batrla, R., Benda, N., Black, K. L., Bokde, A. L. W., Bonuccelli, U., Broich, K., Cacciola, F., Caraci, F., Caruso, G., Castrillo, J., Ceravolo, R., Corbo, M., Corvol, J. -C., Claudio, A., Cummings, J. L., Depypere, H., Duggento, A., Emanuele, E., Escott-Price, V., Federoff, H., Ferretti, M. T., Fiandaca, M., Frank, R. A., Garaci, F., Geerts, H., Giacobini, E., Giorgi, F. S., Goetzl, E. J., Graziani, M., Haberkamp, M., Hanisch, B., Herholz, K., Hernandez, F., Imbimbo, B. P., Kapogiannis, D., Karran, E., Kiddle, S. J., Kim, S. H., Koronyo, Y., Koronyo-Hamaoui, M., Langevin, T., Lehericy, S., Llavero, F., Lorenceau, J., Lucia, A., Mango, D., Mapstone, M., Neri, C., Nistico, R., O'Bryant, S. E., Palermo, G., Perry, G., Ritchie, C., Rossi, S., Saidi, A., Santarnecchi, E., Schneider, L. S., Sporns, O., Toschi, N., Valenzuela, P. L., Vellas, B., Verdooner, S. R., Villain, N., Virecoulon Giudici, K., Watling, M., Welikovitch, L. A., Woodcock, J., Younesi, E., Zugaza, J. L., Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Pisa - Università di Pisa, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Sahlgrenska Academy at University of Gothenburg [Göteborg], University College of London [London] (UCL), UK Dementia Research Institute (UK DRI), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de médecine nucléaire [CHU Pitié-Salpétrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, BIOMARKER, 0301 basic medicine, Oncology, Aging, Neurology, [SDV]Life Sciences [q-bio], Disease, Neurodegenerative, Alzheimer's Disease, Medical and Health Sciences, lcsh:RC346-429, MESH: Cognitive Dysfunction, Alzheimer’s disease, Biomarkers, Mild cognitive impairment, Neurofilament light chain, Subjective memory complainers, Tau, 0302 clinical medicine, Neurofilament Proteins, Medicine and Health Sciences, BRAIN, MESH: Neurofilament Proteins, RISK, Settore FIS/07, NEURODEGENERATION, Cognition, ASSOCIATION, MESH: Follow-Up Studies, Alzheimer's disease, MESH: Amyloid beta-Peptides, MESH: tau Proteins, ALZHEIMERS-DISEASE, POSITIVITY, Neurological, Cohort, Biomarker (medicine), Female, medicine.medical_specialty, Cognitive Neuroscience, tau Proteins, Subjective, Affect (psychology), VALIDATION, lcsh:RC321-571, subjective memory complainers, mild cognitive impairment, biomarkers, s disease, 03 medical and health sciences, memory complainers, Clinical Research, Alzheimer Disease, Internal medicine, NEUROFILAMENT LIGHT-CHAIN, Acquired Cognitive Impairment, medicine, Humans, Cognitive Dysfunction, Vitamin B12, Allele, Alzheimer&#8217, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, Amyloid beta-Peptides, MESH: Humans, business.industry, Research, Prevention, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer Precision Medicine Initiative, COGNITIVE IMPAIRMENT, MESH: Male, Brain Disorders, 030104 developmental biology, MESH: Biomarkers, Dementia, Neurology (clinical), business, INSIGHT-preAD study group, MESH: Female, MESH: Alzheimer Disease, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background Plasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer’s disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE ε4 allele, comorbidities, brain amyloid-β (Aβ) burden, and cognitive scores on plasma NFL and t-Tau concentrations in cognitively healthy individuals with SMC, a condition associated with AD development. Methods Three hundred sixteen and 79 individuals, respectively, have baseline and three-time point assessments (at baseline, 1-year, and 3-year follow-up) of the two biomarkers. Plasma biomarkers were measured with an ultrasensitive assay in a mono-center cohort (INSIGHT-preAD study). Results We show an effect of age on plasma NFL, with women having a higher increase of plasma t-Tau concentrations compared to men, over time. The APOE ε4 allele does not affect the biomarker concentrations while plasma vitamin B12 deficiency is associated with higher plasma t-Tau concentrations. Both biomarkers are correlated and increase over time. Baseline NFL is related to the rate of Aβ deposition at 2-year follow-up in the left-posterior cingulate and the inferior parietal gyri. Baseline plasma NFL and the rate of change of plasma t-Tau are inversely associated with cognitive score. Conclusion We find that plasma NFL and t-Tau longitudinal trajectories are affected by age and female sex, respectively, in SMC individuals. Exploring the influence of biological variables on AD biomarkers is crucial for their clinical validation in blood.

Published
2020

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

Author

Juan Fortea, Sylvain Lehmann, Shahid Zaman, Victor Montal, Tiina Annus, Maria Carmona-Iragui, Sandra Giménez, Jordi Clarimón, Bessy Benejam, Valle Camacho, Teresa Estellés, Susana Fernández, Olivia Belbin, Laura Videla, Anthony J. Holland, Ricardo S. Osorio, Jordi Pegueroles, Alberto Lleó, Isabel Barroeta, Sílvia Valldeneu, Rafael Blesa, Liam R. Wilson, Sofía González-Ortiz, Miren Altuna, Laia Muñoz, Daniel Alcolea, Sebastián Videla, Eduard Vilaplana, Ignacio Illán-Gala, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB), IMIM-Hospital del Mar, Generalitat de Catalunya, University of Cambridge [UK] (CAM), New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), University of Barcelona, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health., Retiveau, Nolwenn, Holland, Anthony [0000-0003-4107-130X], Zaman, Shahid [0000-0003-1639-6014], and Apollo - University of Cambridge Repository

Subjects
Apolipoprotein E, MESH: United Kingdom, positron emission tomography, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, nerve degeneration, Disease, 0302 clinical medicine, middle aged, nuclear magnetic resonance imaging, education.field_of_study, MESH: Middle Aged, adult, General Medicine, Amyloidosis, cohort analysis, MESH: Case-Control Studies, MESH: Amyloid beta-Peptides, MESH: tau Proteins, priority journal, Marcadors bioquímics, Alzheimer disease, medicine.medical_specialty, diagnostic imaging, complication, tau Proteins, Article, cerebrospinal fluid, 03 medical and health sciences, MESH: Cross-Sectional Studies, Apolipoproteins E, Alzheimer Disease, MESH: Spain, cross-sectional study, Humans, neurofilament protein, Cognitive Dysfunction, human, procedures, neurofilament protein L, education, MESH: Prevalence, MESH: Humans, ApoE protein, human, intellectual impairment, Case-control study, MESH: Adult, case control study, medicine.disease, major clinical study, mortality, protein phosphorylation, Cross-Sectional Studies, amyloid beta protein, Case-Control Studies, Positron-Emission Tomography, Down Syndrome, MESH: Alzheimer Disease, Biomarkers, Pediatrics, Down syndrome, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, 030204 cardiovascular system & hematology, MESH: Magnetic Resonance Imaging, MESH: Cognitive Dysfunction, MESH: Fluorodeoxyglucose F18, Neurofilament Proteins, cognitive defect, Prevalence, 030212 general & internal medicine, MESH: Neurofilament Proteins, apolipoprotein E, amyloid beta protein[1-40], Middle Aged, biological marker, MESH: Apolipoproteins E, Magnetic Resonance Imaging, MESH: Positron-Emission Tomography, unclassified drug, fluorodeoxyglucose f 18, neurofilament light chain, female, Biomarker (medicine), medicine.symptom, Cambridge Cognitive Examination for Older Adults with Down Syndrome, Adult, Population, prevalence, Asymptomatic, tau protein, male, blood, Fluorodeoxyglucose F18, medicine, Dementia, controlled study, MESH: Amyloidosis, amyloidosis, Amyloid beta-Peptides, business.industry, amyloid beta protein[1-42], [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Down Syndrome, neurologic disease assessment, Down, Síndrome de, threonine, United Kingdom, Spain, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Alzheimer, MESH: Biomarkers, pathology, business, metabolism
Abstract

Background: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. Methods: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid ß peptides 1–42 and 1–40 and their ratio (Aß1–42/1–40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate. Findings: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aß1–42/1–40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5–54·1), and Alzheimer's disease dementia at 53·7 years (49·5–57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90–100% in the seventh decade of life. Interpretation: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments. Funding: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

Published
2020

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

Author

Sylvain Lehmann, Christophe Hirtz, Shushil Choubey, Alberto Lleó, Mysore Sridhar Santosh, Constance Delaby, Bhavana Veerabhadrappa, Juan Fortea, Jérôme Vialaret, Daniel Alcolea, Centre For Incubation, Innovation, Research and Consultancy (CIIRC), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hospital de la Santa Creu i Sant Pau, Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), and TRANS INTEGRA HEALTH CARE PRIVATE LIMITED

Subjects
Amyloid beta, Amyloid peptides, Clinical Biochemistry, Tau protein, tau Proteins, Disease, 030204 cardiovascular system & hematology, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, MESH: Body Fluids, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Alzheimer Disease, Diagnosis, Medicine, Humans, MESH: Saliva, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Peptide Fragments, Saliva, Body fluid, MESH: Humans, Amyloid beta-Peptides, biology, medicine.diagnostic_test, business.industry, Lumbar puncture, Biochemistry (medical), [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, MESH: Amyloid beta-Peptides, Peptide Fragments, 3. Good health, MESH: tau Proteins, Body Fluids, Blood, 030220 oncology & carcinogenesis, biology.protein, MESH: Biomarkers, Disease Progression, Biomarker (medicine), MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, business, MESH: Alzheimer Disease, Biomarkers
Abstract

International audience; Alzheimer's disease (AD) is an incurable neurodegenerative disease characterized by progressive decline of cognitive abilities. Amyloid beta peptides (Aβ), Tau proteins and the phosphorylated form of the Tau protein, p-Tau, are the core pathological biomarkers of the disease, and their detection for the diagnosis of patients is progressively being implemented. However, to date, their quantification is mostly performed on cerebrospinal fluid (CSF), the collection of which requires an invasive lumbar puncture. Early diagnosis has been shown to be important for disease-modifying treatment, which is currently in development, to limit the progression of the disease. Nevertheless, the diagnosis is often delayed to the point where the disease has already progressed, and the tools currently available do not allow for a systematic follow-up of patients. Thus, the search for a molecular signature of AD in a body fluid such as blood or saliva that can be collected in a minimally invasive way offers hope. A number of methods have been developed for the quantification of core biomarkers, especially in easily accessible fluids such as the blood, that improve their accuracy, specificity and sensitivity. This review summarizes and compares these approaches, focusing in particular on their use for Aβ detection, the earliest biomarker to be modified in the course of AD. The review also discusses biomarker quantification in CSF, blood and saliva and their clinical applications.

Published
2019

7. A TIRF microscopy assay to decode how tau regulates EB's tracking at microtubule ends

Author

Laurence Serre, Eric Denarier, Isabelle Arnal, Angélique Vinit, Emilie Courriol, Virginie Stoppin-Mellet, Elea Prezel, Anne Fourest-Lieuvin, Sacnicte Ramirez-Rios, Julie Delaroche, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), [GIN] Grenoble Institut des Neurosciences (GIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)

Subjects
0301 basic medicine, Microtubule dynamics, Protein family, [SDV]Life Sciences [q-bio], MESH: Microscopy, Fluorescence, TIRF, Microtubules, 03 medical and health sciences, Microtubule, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Microtubule end, Total internal reflection fluorescence microscope, MESH: Humans, biology, MESH: Microtubules, EB3, In vitro, Cell biology, Dynamics, EB1, MESH: tau Proteins, MESH: Microtubule-Associated Proteins, 030104 developmental biology, Tubulin, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Tau, Intracellular organelles, MESH: End-Binding
Abstract

International audience; Tau is a major microtubule-associated protein (MAP) mainly expressed in the brain. Tau binds the lattice of microtubules and favors their elongation and bundling. Recent studies have shown that tau is also a partner of end-binding proteins (EBs) in neurons. EBs belong to the protein family of the plus-end tracking proteins that preferentially associate with the growing plus-ends of microtubules and control microtubule end behavior and anchorage to intracellular organelles. Reconstituted cell-free systems using purified proteins are required to understand the precise mechanisms by which tau influences EB localization on microtubules and how the concerted activity of these two MAPs modulates microtubule dynamics. We developed an in vitro assay combining TIRF microscopy and site-directed mutagenesis to dissect the interaction of tau with EBs and to study how this interaction affects microtubule dynamics. Here, we describe the detailed procedures to purify proteins (tubulin, tau, and EBs), prepare the samples for TIRF microscopy, and analyze microtubule dynamics, and EB binding at microtubule ends in the presence of tau.

Published
2018

8. TIRF assays for real-time observation of microtubules and actin coassembly: Deciphering tau effects on microtubule/actin interplay

Author

Isabelle Arnal, Elea Prezel, Virginie Stoppin-Mellet, Ninon Zala, Auréliane Elie, Laurence Serre, Eric Denarier, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), [GIN] Grenoble Institut des Neurosciences (GIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Arp2/3 complex, MESH: Microscopy, Fluorescence, macromolecular substances, TIRF, Microtubules, 03 medical and health sciences, Microtubule, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cross linker, Actin, Total internal reflection fluorescence microscope, MESH: Humans, biology, Cell growth, MESH: Microtubules, Actin remodeling, Cell biology, Dynamics, MESH: tau Proteins, Crosstalk (biology), MESH: Microtubule-Associated Proteins, 030104 developmental biology, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Tau
Abstract

International audience; Microtubule and actin cytoskeletons are key players in vital processes in cells. Although the importance of microtubule-actin interaction for cell development and function has been highlighted for years, the properties of these two cytoskeletons have been mostly studied separately. Thus we now need procedures to simultaneously assess actin and microtubule properties to decipher the basic mechanisms underlying microtubule-actin crosstalk. Here we describe an in vitro assay that allows the coassembly of both filaments and the real-time observation of their interaction by TIRF microscopy. We show how this assay can be used to demonstrate that tau, a neuronal microtubule-associated protein, is a bona fide actin-microtubule cross-linker. The procedure relies on the use of highly purified proteins and chemically passivated perfusion chambers. We present a step-by-step protocol to obtain actin and microtubule coassembly and discuss the major pitfalls. An ImageJ macro to quantify actin and microtubule interaction is also provided.

Published
2018

9. Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phosphorylation of tau in the brain of FTDP-17 transgenic mice

Author

Wolfgang H. Oertel, Bertrand Friguet, Gesine Respondek, Günter U. Höglinger, Matthias Höllerhage, Agathe Tarze, Stefanie Müssner, Mohamed Salama, Christel Depienne, Agnès Rastetter, Anderson de Andrade, Pierre Champy, Elizabeth Sumi Yamada, Guellaen, Georges, Experimental Neurology, Philipps University, Experimental Neuropathology Laboratory, University Hospital João de Barros Barreto-Federal University of Para - Universidade Federal do Pará - UFPA [Belém, Brazil] (UFPA), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Department of Neurology, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Biologie Cellulaire du vieillissement, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR83, Laboratoire de Pharmacognosie (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Deutsche Forschungsgemeinschaft (HO2402/6-1, HO2402/8-1), the German Ministry of Education and Research (BMBF EF 10-54), the Centre National de la Recherche Scientifique (CNRS), a Marie Curie Incoming International Fellowship (21996 to E.S.Y.) and the German Academic Exchange Service (DAAD to A.C.F.d.A.)., University Hospital João de Barros Barreto-Federal University of Para - Universidade Federal do Para [Belem - Brésil], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Intégrative (IFR-BI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Neurons, pharmacology [Enzyme Inhibitors], drug effects [Gene Expression Regulation], genetics [Gene Expression Regulation], drug effects [Microglia], MESH: Dose-Response Relationship, Drug, Mice, Lactones, chemistry.chemical_compound, 0302 clinical medicine, MESH: Animals, Phosphorylation, pharmacology [Furans], Enzyme Inhibitors, genetics [Arginine], Neurons, 0303 health sciences, Kinase, Neurodegeneration, neurodegeneration, MESH: Arginine, Tryptophan, Brain, MESH: Gene Expression Regulation, Mitochondria, MESH: tau Proteins, Cell biology, MESH: Microglia, Neurology, Biochemistry, MESH: Enzyme Inhibitors, drug effects [Brain], Microglia, genetics [Tryptophan], Tauopathy, Microtubule-Associated Proteins, MESH: Lactones, Genetically modified mouse, MESH: Mutation, MESH: Mice, Transgenic, MESH: Mitochondria, Annonacin, Mice, Transgenic, genetics [Mutation], MAPT protein, human, tau Proteins, Biology, Arginine, MESH: Brain, 03 medical and health sciences, drug effects [Phosphorylation], Developmental Neuroscience, MESH: Mice, Inbred C57BL, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, drug effects [Neurons], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ddc:610, Mortality, genetics [Phosphorylation], Furans, MESH: Mice, MESH: Tryptophan, 030304 developmental biology, MESH: Humans, MESH: Mortality, MESH: Phosphorylation, Dose-Response Relationship, Drug, Cyclin-dependent kinase 5, tauopathy, MESH: Furans, metabolism [Microtubule-Associated Proteins], annonacin, metabolism [Mitochondria], medicine.disease, Mice, Inbred C57BL, MESH: Microtubule-Associated Proteins, genetics [tau Proteins], Somatodendritic compartment, Gene Expression Regulation, chemistry, environmental neurotoxin, metabolism [Brain], Mutation, pharmacology [Lactones], genetics [Mitochondria], microtubule-associated protein tau, 030217 neurology & neurosurgery
Abstract

International audience; Both genetic and environmental factors likely contribute to the neuropathology of tauopathies, but it remains unclear how specific genetic backgrounds affect the susceptibility towards environmental toxins. Mutations in the tau gene have been associated with familial tauopathies, while annonacin, a plant-derived mitochondrial inhibitor, has been implicated in an environmental form of tauopathy. We therefore determined whether there was a pathogenic synergy between annonacin exposure and the expression of the R406W-tau mutation in transgenic mice. We found that annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas in R406W(+/+) mice as opposed to mice that had only the endogenous mouse tau (R406W(-/-)). Western blot analysis demonstrated a concomitant increase in total tau protein without increase in tau mRNA, but reduced proteasomal proteolytic activity in R406W(+/+), but not R406W(-/-) mice, upon annonacin-treatment. Phosphorylated tau levels exceeded the increase in total tau protein, along with increased levels of different tau kinases, foremost a striking increase in the p25/p35 ratio, known to activate the tau kinase Cdk5. In summary, we observed a synergistic interaction between annonacin exposure and the presence of the R406W-tau mutation, which resulted in reduced degradation, increased phosphorylation and redistribution of neuronal tau.

Published
2014

10. Tunneling nanotubes: A possible highway in the spreading of tau and other prion-like proteins in neurodegenerative diseases

Author

Guiliana Soraya Victoria, Karen Duff, Saïda Abounit, Chiara Zurzolo, Jessica W. Wu, Abounit, S., Wu, J. W., Duff, K., Victoria, G. S., Zurzolo, C., Trafic membranaire et Pathogénèse, Institut Pasteur [Paris], Columbia University Medical Center (CUMC), Columbia University [New York], The CAR-NOT-ICSA-PMI and the Equipe FRM (Fondation Recherche Medicale) 2014 (DEQ20140329557) to C.Z. K.D and J.W.Wwere supported by National Institute of Health NS081555. G.S.V. was supported by Bourse Pasteur-Roux, Institut Pasteur, Paris., ANR-14-JPCD-0002,Neutargets,Targeting the propagation of pathogenic protein assemblies in neurodegenerative disease(2014), and Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, Huntingtin, [SDV]Life Sciences [q-bio], Mutant, tau Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein aggregation, HeLa Cell, Prion Protein, Biochemistry, Prion Proteins, MESH: Neurodegenerative Diseases, Amyloidogenic Proteins, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, MESH: Animal, Animals, Humans, Secretion, Prion protein, MESH: Mice, Extra Views, MESH: Humans, Nanotubes, Neurodegenerative Disease, Chemistry, Extramural, Animal, tau Protein, Neurodegenerative Diseases, Cell Biology, MESH: Prion Proteins, MESH: tau Proteins, 030104 developmental biology, Infectious Diseases, MESH: HeLa Cells, Biophysics, MESH: Nanotubes, Intracellular, HeLa Cells, Human
Abstract

International audience; The mechanisms of intercellular spreading of amyloidogenic proteins involved inneurodegenerative diseases have yet to be fully elucidated. While secretion has been implicated inthe transfer of many proteins, including prions anda-synuclein, tunneling nanotubes (TNTs) havealso been demonstrated for prions and mutant Huntingtin. Here, we provide further evidence that Tauaggregates, which have been demonstrated to predominantly be transferred via secretion, can also befound in TNTs. Additionally, cells that have taken up Tau have increased TNT formation. Coupledwith previous evidence that other amyloidogenic aggregates also induce TNT formation we proposethat misfolded protein aggregates can, through a common mechanism, promote the formation ofTNTs and thereby their own intercellular transfer, contributing to the propagation of pathology

Published
2016

11. Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation

Author

Martine Doco-Fenzy, Sylvie Jaillard, Odile Boute, Christèle Dubourg, Patrick Edery, Bénédicte Duban-Bedu, Véronique David, Joris Andrieux, Catherine Vincent-Delorme, Isabelle Mortemousque, Albert David, Anne Moncla, Mylène Beri, Dominique Martin-Coignard, Caroline Schluth-Bolard, Nicole Philip, Annick Toutain, Séverine Drunat, Emilie Landais, Sylvie Odent, Chantal Missirian, Cédric Le Caignec, Damien Sanlaville, Jean Mosser, Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), UFR de Médecine, Université de Reims Champagne-Ardenne (URCA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service de génétique, Centre Hospitalier Le Mans (CH Le Mans), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Laboratoire de Biochimie Génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Plate-forme transcriptome, Université de Rennes (UR), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), This research was supported by grants from FEDER, DHOS and STIC 2004/EGMAR., Laboratoire de Génétique Moléculaire, Hôpital Pontchaillou, Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hôpital Saint Vincent de Paul-GHICL, Service de Génétique Clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-hôpital Sud, De Villemeur, Hervé, and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
MESH: Chromosome Deletion, Developmental Disabilities, Chromosome Disorders, tau Proteins, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Base Sequence, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, MESH: Mental Retardation, Intellectual Disability, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Genetics, medicine, Humans, Copy-number variation, Allele, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genotyping, Genetics (clinical), 030304 developmental biology, MESH: Chromosome Disorders, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, MESH: Humans, Base Sequence, MESH: Muscle Hypotonia, business.industry, Chromosome, General Medicine, Microdeletion syndrome, medicine.disease, 17q21.31 microdeletion syndrome, Hypotonia, MESH: tau Proteins, MESH: France, MESH: Developmental Disabilities, Muscle Hypotonia, France, Chromosome Deletion, medicine.symptom, Abnormality, business, MESH: Chromosomes, Human, Pair 17, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17
Abstract

International audience; Chromosome 17q21.31 microdeletion was one of the first genomic disorders identified by chromosome microarrays. We report here the clinical and molecular characterization of a new series of 14 French patients with this microdeletion syndrome. The most frequent clinical features were hypotonia, developmental delay and facial dysmorphism, but scaphocephaly, prenatal ischemic infarction and perception deafness were also described. Genotyping of the parents showed that the parent from which the abnormality was inherited carried the H2 inversion polymorphism, confirming that the H2 allele is necessary, but not sufficient to generate the 17q21.31 microdeletion. Previously reported molecular analyses of patients with 17q21.31 microdeletion syndrome defined a 493 kb genomic fragment that was deleted in most patients after taking into account frequent copy number variations in normal controls, but the deleted interval was significantly smaller (205 kb) in one of our patients, encompassing only the MAPT, STH and KIAA1267 genes. As this patient presents the classical phenotype of 17q21.31 syndrome, these data make it possible to define a new minimal critical region of 160.8 kb, strengthening the evidence for involvement of the MAPT gene in this syndrome.

Published
2011

12. Upper Airway Dysfunction of Tau-P301L Mice Correlates with Tauopathy in Midbrain and Ponto-Medullary Brainstem Nuclei

Author

Christian Gestreau, Peter Borghgraef, Georg M. Stettner, Lies Gielis, Clément Menuet, Mathias Dutschmann, Fred Van Leuven, Gérard Hilaire, Herman Devijver, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and LEGT-EGG

Subjects
Aging, Pathology, MESH: Pulmonary Ventilation, Mice, 0302 clinical medicine, Mesencephalon, MESH: Aging, MESH: Animals, Phosphorylation, 0303 health sciences, biology, General Neuroscience, Articles, MESH: tau Proteins, Plethysmography, medicine.anatomical_structure, Tauopathies, MESH: Respiration Disorders, MESH: Tauopathies, Brainstem, Tauopathy, medicine.symptom, Hypercapnia, medicine.medical_specialty, MESH: Mutation, MESH: Mice, Transgenic, Tau protein, Hyperphosphorylation, Mice, Transgenic, tau Proteins, Periaqueductal gray, Midbrain, 03 medical and health sciences, MESH: Plethysmography, medicine, Neuropil, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Mice, 030304 developmental biology, MESH: Phosphorylation, MESH: Mesencephalon, Respiration Disorders, medicine.disease, Disease Models, Animal, Mutation, MESH: Brain Stem, biology.protein, MESH: Disease Models, Animal, Pulmonary Ventilation, Neuroscience, 030217 neurology & neurosurgery, Brain Stem
Abstract

Tauopathy comprises hyperphosphorylation of the microtubule-associated protein tau, causing intracellular aggregation and accumulation as neurofibrillary tangles and neuropil treads. Some primary tauopathies are linked to mutations in theMAPTgene coding for protein tau, but most are sporadic with unknown causes. Also, in Alzheimer's disease, the most frequent secondary tauopathy, neither the cause nor the pathological mechanisms and repercussions are understood. Transgenic mice expressing mutant Tau-P301L suffer cognitive and motor defects and die prematurely from unknown causes. Here,in situelectrophysiology in symptomatic Tau-P301L mice (7–8 months of age) revealed reduced postinspiratory discharges of laryngeal motor outputs that control laryngeal constrictor muscles. Under high chemical drive (hypercapnia), postinspiratory discharge was nearly abolished, whereas laryngeal inspiratory discharge was increased disproportionally. The latter may suggest a shift of postinspiratory laryngeal constrictor activity into inspiration.In vivodouble-chamber plethysmography of Tau-P301L mice showed significantly reduced respiratory airflow but significantly increased chest movements during baseline breathing, but particularly in hypercapnia, confirming a significant increase in inspiratory resistive load. Histological analysis demonstrated hyperphosphorylated tau in brainstem nuclei, directly or indirectly involved in upper airway motor control (i.e., the Kölliker–Fuse, periaqueductal gray, and intermediate reticular nuclei). In contrast, young Tau-P301L mice did not show breathing disorders or brainstem tauopathy. Consequently, in aging Tau-P301L mice, progressive upper airway dysfunction is linked to progressive tauopathy in identified neural circuits. Because patients with tauopathy suffer from upper airway dysfunction, the Tau-P301L mice can serve as an experimental model to study disease-specific synaptic dysfunction in well defined functional neural circuits.

Published
2010

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

Author

Akio Ojida, Guy Lippens, Takashi Sakamoto, Itaru Hamachi, Masa Aki Inoue, Sho Hei Fujishima, Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology (TUMSAT), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Boron Compounds, MESH: Hippocampus, Tau protein, MESH: Boron Compounds, Molecular Probe Techniques, tau Proteins, 010402 general chemistry, Hippocampus, 01 natural sciences, Biochemistry, MESH: Zinc, Catalysis, chemistry.chemical_compound, MESH: Brain, Colloid and Surface Chemistry, Alzheimer Disease, mental disorders, Humans, Phosphorylation, Binding site, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Humans, biology, MESH: Phosphorylation, 010405 organic chemistry, Brain, Neurofibrillary Tangles, General Chemistry, Fluorescence, Phosphorylated Peptide, 0104 chemical sciences, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: tau Proteins, Dissociation constant, MESH: Molecular Probe Techniques, Zinc, Dipicolylamine, chemistry, biology.protein, BODIPY, Molecular probe, MESH: Alzheimer Disease, MESH: Neurofibrillary Tangles
Abstract

International audience; We have developed a new fluorescent binuclear Zn(II) complex for the detection of neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, a representative hallmark of Alzheimer's disease (AD). The probe 1 incorporates a fluorescent BODIPY unit and two Zn(II)-2,2'-dipicolylamine (Dpa) complexes as a binding site for phosphorylated amino acid residues. Using fluorescence titration to evaluate the binding and sensing properties of 1 toward several phosphorylated peptide segments derived from hyperphosphorylated tau protein, we found that 1 binds preferentially to peptides presenting phosphorylated groups at the i and i+4 positions with dissociation constants (K(d)) in the micromolar range. Fluorescence titration with an artificially prepared aggregate of the phosphorylated tau protein (p-Tau) revealed that 1 binds strongly to p-Tau (EC(50) = 9 nM). In contrast, the interactions of 1 were weaker toward artificially prepared aggregates of the nonphosphorylated tau protein (n-Tau; EC(50) = 80 nM) and Abeta(1-42) fibrils (EC(50) = 650 nM). Histological imaging of a hippocampus tissue section obtained from an AD patient revealed that 1 fluorescently visualizes deposits of NFTs and clearly discriminates between NFTs and the amyloid plaques assembled from amyloid-beta peptides, confirming our strategy toward the rational design of a molecular probe for the selective fluorescence detection of NFTs in brain tissue sections.

Published
2009

14. Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2

Author

Markus Zweckstetter, Harindranath Kadavath, Valéry Ozenne, Stefan Bibow, Martin Blackledge, Eckhard Mandelkow, Martin Schwalbe, Jacek Biernat, Malene Ringkjøbing Jensen, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Phosphorylation sites, metabolism [Microtubules], Tau protein, MAPT protein, human, tau Proteins, macromolecular substances, Protein Serine-Threonine Kinases, Biochemistry, Microtubules, MESH: Protein-Serine-Threonine Kinases, Serine, 03 medical and health sciences, 0302 clinical medicine, metabolism [Protein Serine-Threonine Kinases], Microtubule, MESH: Nuclear Magnetic Resonance, Biomolecular, medicine, Humans, Phosphorylation, Nuclear Magnetic Resonance, Biomolecular, 030304 developmental biology, chemistry [Protein-Serine-Threonine Kinases], 0303 health sciences, MESH: Humans, biology, MESH: Phosphorylation, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Kinase, MESH: Microtubules, Neurodegeneration, chemistry [tau Proteins], metabolism [Protein-Serine-Threonine Kinases], medicine.disease, Protein-Serine-Threonine Kinases, metabolism [tau Proteins], Cell biology, MESH: tau Proteins, MARK2 protein, human, ddc:540, biology.protein, chemistry [Protein Serine-Threonine Kinases], chemistry [Microtubules], 030217 neurology & neurosurgery
Abstract

International audience; Tau protein plays an important role in neuronal physiology and Alzheimer's neurodegeneration. Its abilities to aggregate abnormally, to bind to microtubules (MTs), and to promote MT assembly are all influenced by phosphorylation. Phosphorylation of serine residues in the KXGS motifs of Tau's repeat domain, crucial for MT interactions and aggregation, is facilitated most efficiently by microtubule-associated protein/microtubule affinity-regulating kinases (MARKs). Here we applied high-resolution nuclear magnetic resonance analysis to study the kinetics of phosphorylation of Tau by MARK2 and its impact on the structure and microtubule binding of Tau. We demonstrate that MARK2 binds to the N-terminal tail of Tau and selectively phosphorylates three major and five minor serine residues in the repeat domain and C-terminal tail. Structural changes induced by phosphorylation of Tau by MARK2 are highly localized in the proximity of the phosphorylation site and do not affect the global conformation, in contrast to phosphorylation in the proline-rich region. Furthermore, single-residue analysis of binding of Tau to MTs provides support for a model in which Tau's hot spots of MT interaction bind independently of each other and are differentially affected by phosphorylation.

Published
2013

15. Connective tissue growth factor regulates interneuron survival and information processing in the olfactory bulb

Author

Hannah Monyer, Pierre-Marie Lledo, Jakob von Engelhardt, Hiroshi Kaneko, Françoise Lazarini, Konstantin Khodosevich, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University Medical Center Heidelberg, Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Life insurance company ‘‘AG2R-LaMondiale,’’, the Agence Nationale de la Recherche ‘‘ANR-BLAN-SVSE4-LS-110624,’’, ‘‘ANR-09-NEUR-004’’ in the frame of ‘‘ERA-NET NEURON’’ of the FP7 program by the European Commission, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, genetics [Receptors, Odorant], genetics [Gene Expression Regulation], Receptors, Odorant, Mice, 0302 clinical medicine, Discrimination, Psychological, metabolism [MicroRNAs], MESH: Smell, MESH: Animals, MESH: Discrimination (Psychology), MESH: Nerve Tissue Proteins, genetics [Cell Survival], 0303 health sciences, integumentary system, Neurogenesis, MESH: Interneurons, MESH: tau Proteins, Smell, physiology [Discrimination, Psychological], neurogenesis, MESH: Cell Survival, Sensory Thresholds, Memory, Long-Term, genetics [Smell], Neuroscience(all), Connective tissue, physiology [Interneurons], tau Proteins, Olfaction, Transfection, biocytin, genetics [Protein-Serine-Threonine Kinases], Article, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, Organ Culture Techniques, MESH: Memory, Long-Term, Humans, metabolism [Nerve Tissue Proteins], MESH: Humans, MESH: Odors, Lysine, metabolism [Bromodeoxyuridine], Receptor, Transforming Growth Factor-beta Type II, physiology [Sensory Thresholds], Mice, Inbred C57BL, genetics [tau Proteins], Luminescent Proteins, genetics [Synaptic Potentials], nervous system, metabolism [Connective Tissue Growth Factor], Odorants, genetics [Receptors, Transforming Growth Factor beta], MESH: Sensory Thresholds, Neuroscience, Receptors, Transforming Growth Factor beta, MESH: MicroRNAs, MESH: Female, 030217 neurology & neurosurgery, animal diseases, MESH: Synaptic Potentials, genetics [Luminescent Proteins], genetics [RNA, Small Interfering], physiology [Memory, Long-Term], MESH: Animals, Newborn, MESH: RNA, Small Interfering, MESH: Receptors, Odorant, genetics [MicroRNAs], RNA, Small Interfering, genetics [Nerve Tissue Proteins], Cell Line, Transformed, MESH: Bromodeoxyuridine, General Neuroscience, musculoskeletal, neural, and ocular physiology, Synaptic Potentials, analogs & derivatives [Lysine], Protein-Serine-Threonine Kinases, Olfactory Bulb, MESH: Gene Expression Regulation, metabolism [Lysine], Olfr16 protein, mouse, medicine.anatomical_structure, Female, MESH: Luminescent Proteins, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Receptors, Transforming Growth Factor beta, olfaction, MESH: Connective Tissue Growth Factor, MESH: Olfactory Bulb, Interneuron, Cell Survival, MESH: Mice, Transgenic, Sensory system, Mice, Transgenic, Nerve Tissue Proteins, interneuron, Biology, Protein Serine-Threonine Kinases, Inhibitory postsynaptic potential, cytology [Olfactory Bulb], physiology [Olfactory Bulb], Interneurons, MESH: Mice, Inbred C57BL, MESH: Analysis of Variance, medicine, Animals, MESH: Lysine, ddc:610, metabolism [RNA, Small Interfering], MESH: Cell Line, Transformed, metabolism [Luminescent Proteins], metabolism [Receptors, Odorant], MESH: Mice, 030304 developmental biology, Analysis of Variance, MESH: Transfection, Connective Tissue Growth Factor, genetics [Connective Tissue Growth Factor], MESH: Male, MESH: Organ Culture Techniques, Olfactory bulb, CTGF, MicroRNAs, Gene Expression Regulation, Animals, Newborn, Bromodeoxyuridine
Abstract

International audience; Neurogenesis underlies plastic changes in defined neuronal circuits in the postnatal and adult brain. Here we identify connective tissue growth factor (CTGF) as a critical factor in the mouse olfactory bulb (OB) in determining the efficiency of incorporation of postnatally born inhibitory neurons, thus gating the output of glomeruli, the first relay station of olfactory processing in the brain. In the OB, CTGF expression was restricted to prenatally born external tufted cells. CTGF enhanced the proapoptotic activity of glial-derived TGF-β2, decreasing the survival of periglomerular inhibitory neurons. Changes in CTGF expression levels in the OB led to modifications in local neuronal circuitry and olfactory behaviors. We show that the odorant-specific recruitment of distinct glomeruli resulted in enhanced local CTGF expression levels in the activated glomeruli. Collectively our data reveal a molecular mechanism controlling the survival of defined postnatally born neurons, thus adapting neuronal integration to the sensory experiences.

Published
2013

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

Author

Edmond Moukari, Stéphane Lehéricy, Michel Bottlaender, Bruno Dubois, Olivier Colliot, Leonardo Cruz de Souza, Foudil Lamari, Guillaume Dorothée, Marie Chupin, Pierre Aucouturier, Fabian Corlier, Marie Sarazin, Renaud Maroy, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Système immunitaire et neuroinflammation [CRSA], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service Hospitalier Frédéric Joliot (SHFJ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Pathology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cerebral disorder, Subclass, Immunoglobulin G, 0302 clinical medicine, Cerebrospinal fluid, MESH: Aged, 80 and over, MESH: Radionuclide Imaging, Phosphorylation, Central nervous system disease, Aged, 80 and over, MESH: Aged, MESH: Immunoglobulin G, 0303 health sciences, MESH: Middle Aged, Brain, Middle Aged, MESH: Amyloid beta-Peptides, MESH: Immunoglobulin M, 3. Good health, MESH: tau Proteins, Alzheimer's disease, Antibody, Alzheimer disease, medicine.medical_specialty, Amyloid, tau Proteins, Biology, Antibodies, 03 medical and health sciences, MESH: Brain, Arts and Humanities (miscellaneous), Antigen, medicine, Humans, Radionuclide Imaging, Aged, 030304 developmental biology, Amyloid beta-Peptides, MESH: Humans, MESH: Phosphorylation, MESH: Antibodies, Posterior cortical atrophy, medicine.disease, Nervous system diseases, MESH: Male, Immunoglobulin M, Degenerative disease, Immunology, biology.protein, MESH: Biomarkers, Neurology (clinical), Biomarkers, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract

International audience; OBJECTIVE: To compare serum antiamyloid-β (Aβ) antibodies in typical and atypical Alzheimer disease (AD). DESIGN: Preliminary observations. SUBJECTS: Thirteen patients with AD, 8 patients with posterior cortical atrophy with evidence of AD (PCA-AD) pathophysiological process by both cerebrospinal fluid (CSF) biomarkers and amyloid imaging, and 12 age-matched control individuals. INTERVENTIONS: The class and subclass levels of serum anti-Aβ antibodies were measured using an oligomer-based enzyme-linked immunosorbent assay. This method allowed measuring both free antibodies and, after acidic treatment, the total fraction that includes all antibodies complexed with circulating Aβ40/42 and any cross-reacting antigen. RESULTS: Anti-Aβ IgG were restricted to the IgG1 and IgG3 subclasses. Their total levels were strikingly lower and more homogeneous in patients with PCA compared with both typical AD and controls, while biomarkers of amyloid deposition (CSF Aβ42 and positron emission tomography amyloid imaging) were similar in patients with AD and patients with PCA. CONCLUSIONS: Serum anti-Aβ IgG1 and IgG3 antibodies differ between distinct forms of AD. Its significance is discussed for possible implications as immune effectors in the specific pathophysiology of AD variants.

Published
2012

17. Towards understanding the phosphorylation code of tau

Author

Laziza Amniai, Arnaud Leroy, Guy Lippens, Alain Sillen, Isabelle Landrieu, Jean Michel Wieruszeski, Université Lille Nord de France (COMUE), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie Appliquée, Université Paris-Sud - Paris 11 (UP11), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
inorganic chemicals, Magnetic Resonance Spectroscopy, Tau protein, tau Proteins, macromolecular substances, Biochemistry, environment and public health, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Alzheimer Disease, medicine, Animals, Humans, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylation, 030304 developmental biology, 0303 health sciences, MESH: Humans, biology, MESH: Phosphorylation, Chemistry, Kinase, MESH: Magnetic Resonance Spectroscopy, Nuclear magnetic resonance spectroscopy, medicine.disease, In vitro, Cell biology, MESH: tau Proteins, enzymes and coenzymes (carbohydrates), Recombinant DNA, biology.protein, bacteria, Alzheimer's disease, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract

International audience; We describe our efforts to combine in vitro enzymatic reactions with recombinant kinases to phosphorylate the neuronal tau protein, and NMR spectroscopy to unravel the resulting phosphorylation pattern in both qualitative and quantitative manners. This approach, followed by functional assays with the same samples, gives access to the complex phosphorylation code of tau. As a result, we propose a novel hypothesis for the link between tau (hyper)phosphorylation and aggregation.

Published
2012

18. Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-β peptide

Author

Frédéric Checler, Eric Sjoberg, Joseph D. Buxbaum, David J. Lockhart, Kenneth J. Valenzano, Katsuhiko Yanagisawa, Sam Gandy, Hadis Williams, Serene Keilani, Richie Khanna, Yi Lun, Brandon Wustman, Anthony Stevens, Departments of Neurology and Psychiatry, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Amicus Therapeutics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Friedman Brain Institute, Mount Sinai, National Center for Geriatrics and Gerontology, and Research Institute

Subjects
G(M2) Ganglioside, Vacuole, MESH: Mice, Knockout, Pathogenesis, MESH: Spinal Cord, Mice, 0302 clinical medicine, Gangliosides, Amyloid precursor protein, MESH: Animals, MESH: Brain Chemistry, MESH: Lipid Metabolism, Mice, Knockout, 0303 health sciences, Medulla Oblongata, General Neuroscience, MESH: G(M2) Ganglioside, Sandhoff Disease, Articles, MESH: Infant, Immunohistochemistry, MESH: Amyloid beta-Peptides, Cell biology, MESH: tau Proteins, Substantia Nigra, Biochemistry, Spinal Cord, MESH: Young Adult, Child, Preschool, alpha-Synuclein, Adult, Endosome, MESH: Hexosaminidase B, Blotting, Western, MESH: Substantia Nigra, Substantia nigra, tau Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Sandhoff disease, Biology, 03 medical and health sciences, Young Adult, Hexosaminidase B, MESH: Mice, Inbred C57BL, MESH: Medulla Oblongata, MESH: alpha-Synuclein, medicine, MESH: Blotting, Western, Animals, Humans, MESH: Mice, 030304 developmental biology, MESH: Gangliosides, Brain Chemistry, Ganglioside, MESH: Humans, Amyloid beta-Peptides, MESH: Child, Preschool, Infant, MESH: Adult, MESH: Immunohistochemistry, medicine.disease, Lipid Metabolism, HEXB, Mice, Inbred C57BL, biology.protein, MESH: Sandhoff Disease, Lysosomes, 030217 neurology & neurosurgery, MESH: Lysosomes
Abstract

Alterations in the lipid composition of endosomal–lysosomal membranes may constitute an early event in Alzheimer's disease (AD) pathogenesis. In this study, we investigated the possibility that GM2 ganglioside accumulation in a mouse model of Sandhoff disease might be associated with the accumulation of intraneuronal and extracellular proteins commonly observed in AD. Our results show intraneuronal accumulation of amyloid-β peptide (Aβ)-like, α-synuclein-like, and phospho-tau-like immunoreactivity in the brains of β-hexosaminidase knock-out (HEXBKO) mice. Biochemical and immunohistochemical analyses confirmed that at least some of the intraneuronal Aβ-like immunoreactivity (iAβ-LIR) represents amyloid precursor protein C-terminal fragments (APP-CTFs) and/or Aβ. In addition, we observed increased levels of Aβ40 and Aβ42 peptides in the lipid-associated fraction ofHEXBKO mouse brains, and intraneuronal accumulation of ganglioside-bound Aβ (GAβ) immunoreactivity in a brain region-specific manner. Furthermore, α-synuclein and APP-CTFs and/or Aβ were found to accumulate in different regions of the substantia nigra, indicating different mechanisms of accumulation or turnover pathways. Based on the localization of the accumulated iAβ-LIR to endosomes, lysosomes, and autophagosomes, we conclude that a significant accumulation of iAβ-LIR may be associated with the lysosomal–autophagic turnover of Aβ and fragments of APP-containing Aβ epitopes. Importantly, intraneuronal GAβ immunoreactivity, a proposed prefibrillar aggregate found in AD, was found to accumulate throughout the frontal cortices of postmortem human GM1 gangliosidosis, Sandhoff disease, and Tay–Sachs disease brains. Together, these results establish an association between the accumulation of gangliosides, autophagic vacuoles, and the intraneuronal accumulation of proteins associated with AD.

Published
2012

19. Cerebrospinal fluid collection tubes: a critical issue for Alzheimer disease diagnosis

Author

Gabor G. Kovacs, Eric Thouvenot, Sylvain Lehmann, Pierre Krolak-Salmon, Benaïssa Elmoualij, Catherine Thomas-Antérion, Susanna Schraen, Armand Perret-Liaudet, Arnaud Coudreuse, Benoit Dumont, Hugo Vanderstichele, Audrey Gabelle, Willy Zorzi, Isabelle Quadrio, Jacques Touchon, Yannick Tholance, Olivier Moreaud, Mathieu Pelpel, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technical and QA Department, Innogenetics SARL, ADx Neurosciences (ADx), ADx Neurosciences NV, Institute of Human Histology-CRPP (CRPP), Université de Liège, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Laboratoire de Psychologie et NeuroCognition (LPNC), Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Unité de Neuropsychologie, CHU Grenoble, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Mémoire de Ressource et Recherche (CMRR), CHU Saint-Etienne-Hôpital Bellevue, Centre de Transfert de Technologie du Mans (CTTM), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)

Subjects
Pathology, medicine.medical_specialty, Clinical Biochemistry, tau Proteins, Cerebrospinal fluid collection, Polypropylenes, MESH: Spectroscopy, Fourier Transform Infrared, Specimen Handling, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Clinical work, Alzheimer Disease, Spectroscopy, Fourier Transform Infrared, medicine, Total Tau Protein, Humans, MESH: Specimen Handling, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, MESH: Humans, Amyloid beta-Peptides, Calorimetry, Differential Scanning, business.industry, Biochemistry (medical), MESH: Calorimetry, Differential Scanning, MESH: Biological Markers, Lumbar puncture needle, MESH: Polypropylenes, medicine.disease, MESH: Amyloid beta-Peptides, 3. Good health, MESH: tau Proteins, Polyethylene, Csf biomarkers, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, business, MESH: Polyethylene, 030217 neurology & neurosurgery, MESH: Alzheimer Disease, Biomarkers
Abstract

To the Editor: Total tau protein (hTau),1 its phosphorylated isoform (p-Tau181P), and Aβ1–42 peptides are the currently accepted cerebrospinal fluid (CSF) biomarkers used as aids in the diagnosis of Alzheimer disease (1). Although polypropylene (PP) was previously reported as the best material for CSF collection tubes (2), heterogeneity in CSF Aβ1–42 values was observed with different PP sampling tubes (3). Because the recommendation to use PP tubes did not lead to standardization of clinical cutoff values (4), we decided to fully address this issue by comparing various types of tubes within an actual clinical work flow and by analyzing the material of different commercially available PP tubes. In the framework of an ethically approved study, we collected CSF samples from 12 patients directly (from the lumbar puncture needle) into 2 PP tubes [BD catalog no. 352096 (BD-PP); Sarstedt catalog no. 62.610.201 (ST-PP)], 1 hemolysis polyethylene tube [Fisher Scientific catalog no. ref.W1773X (HE-PE)], and 1 polystyrene tube [BD catalog no. 352095 (BD-PS)]. CSF biomarker concentrations were measured in parallel in these 4 types of tubes with Innogenetics INNOTEST® kits. We extended this analysis by comparing the results obtained with 11 different commercially available collection tubes labeled as “PP” for a series of fresh (unfrozen) …

Published
2012

20. Time sequence of oxidative stress in the brain from transgenic mouse models of Alzheimer's disease related to the amyloid-β cascade

Author

Charles Ramassamy, Abdenour Belkacemi, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Faculté de Médecine, Université Laval [Québec] (ULaval), and Financial support from the Natural Sciences and Engineering Research Council of Canada (NSERC) is gratefully acknowledged

Subjects
Gerontology, Genetically modified mouse, Apolipoprotein E, MESH: Oxidation-Reduction, Time Factors, MESH: Gene Expression, MESH: Mutation, MESH: Mice, Transgenic, Transgene, BACE1-AS, Gene Expression, Mice, Transgenic, tau Proteins, medicine.disease_cause, Biochemistry, Presenilin, Mice, MESH: Brain, Alzheimer Disease, Physiology (medical), Amyloid precursor protein, medicine, Animals, Humans, MESH: Animals, MESH: Mice, Free-radical theory of aging, Amyloid beta-Peptides, MESH: Oxidative Stress, MESH: Humans, biology, Chemistry, MESH: Time Factors, Presenilins, Brain, MESH: Amyloid beta-Peptides, MESH: Presenilins, MESH: tau Proteins, Disease Models, Animal, Oxidative Stress, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Mutation, biology.protein, MESH: Disease Models, Animal, Oxidation-Reduction, Neuroscience, Oxidative stress, MESH: Alzheimer Disease
Abstract

International audience; Alzheimer's disease (AD) is a multifactorial disorder characterized by the presence of amyloid plaques and neurofibrillary tangles (NFTs). Rare early-onset forms of AD are associated with autosomal dominant mutations in the amyloid precursor protein gene, presenilin 1 gene, or presenilin 2 gene. The late-onset form of the disease (LOAD) is the most common form. The causes of LOAD are not yet clarified, but several environmental and genetic risk factors have been identified. Numerous studies have highlighted a role for free radical-mediated injury to brain regions of this illness. In addition, studies from mild cognitive impairment patients suggest that oxidative stress is an early event in the pathogenesis of AD. The associations between these markers of free radical damage and the pathogenic cascades involved in AD are complex. Over the past 2 decades, a number of mouse models have been created to recapitulate the major neuropathological hallmarks of AD, namely amyloid plaques and NFTs. These mice recapitulate many, although not all, of the key features of AD. Some strains of transgenic mice develop amyloid plaques, some accumulate NFTs, and some do both. Here we review the evidence for increased free radical-mediated damage to the brain with particular attention to the stage of the disease in various transgenic models of AD related to the amyloid-β cascade.

Published
2012

21. Raphé tauopathy alters serotonin metabolism and breathing activity in terminal Tau.P301L mice: possible implications for tauopathies and Alzheimer's disease

Author

Peter Borghgraef, Mathias Dutschmann, Christian Gestreau, Gérard Hilaire, Fred Van Leuven, Lies Gielis, Nicolas Voituron, Clément Menuet, Anne-Marie Lajard, Valéry Matarazzo, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Experimental Genetics Group, Department of Human Genetics, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut de Biologie du Développement de Marseille (IBDM), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pulmonary and Respiratory Medicine, Serotonin, medicine.medical_specialty, Pathology, Physiology, MESH: Mice, Transgenic, Tau protein, Mice, Transgenic, tau Proteins, Mice, 03 medical and health sciences, Lethargy, 0302 clinical medicine, Alzheimer Disease, Internal medicine, MESH: Plethysmography, medicine, Animals, Humans, MESH: Animals, Respiratory system, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Mice, 030304 developmental biology, Nucleus raphe magnus, 0303 health sciences, MESH: Humans, biology, Raphe, General Neuroscience, MESH: Raphe Nuclei, medicine.disease, 3. Good health, MESH: tau Proteins, Plethysmography, Endocrinology, Tauopathies, MESH: Tauopathies, Forebrain, Respiratory Mechanics, biology.protein, Raphe Nuclei, MESH: Respiratory Mechanics, MESH: Serotonin, Tauopathy, Brainstem, Psychology, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract

International audience; Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the tauopathy in the forebrain, but most also display early brainstem tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe tauopathy in Kolliker-Fuse, raphé obscurus and raphé magnus nuclei but not in medullary respiratory-related areas. Although the raphé tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphé tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease.

Published
2011

22. Switching reversibility to irreversibility in glycogen synthase kinase 3 inhibitors: clues for specific design of new compounds

Author

Carmen Gil, Pablo D. Dans, Ana Martínez, F. Javier Luque, Santiago Conde, Concepción Pérez, Valle Palomo, Daniel I. Perez, Instituto de Quimica Médica (CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP), Departamento de Fisicoquímica e Instituto de Biomedicina, Facultad de farmacia-Universidad de Barcelona, and Financial support from MICINN and ISCiii (projects nos. SAF2009-13015-CO2-01, SAF2008-05595, SAF2006-01249 and RD07-0060/0015) and computational facilities from the CESCA are also acknowledged. D. I. P. acknowledges a postdoctoral grant to the CSIC (JAEDoc program) and V. P. a predoctoral grant (JAEPre program).

Subjects
Models, Molecular, MESH: Neurons, Plasma protein binding, MESH: Ketones, Pharmacology, MESH: Drug Design, 01 natural sciences, MESH: Receptors, Neurotransmitter, MESH: Neurodegenerative Diseases, Glycogen Synthase Kinase 3, Mice, Adenosine Triphosphate, MESH: Structure-Activity Relationship, GSK-3, Cerebellum, Drug Discovery, MESH: Adenosine Triphosphate, MESH: Animals, Phosphorylation, Receptor, MESH: Glycogen Synthase Kinase 3, Neurons, 0303 health sciences, Chemistry, Neurodegenerative Diseases, Stereoisomerism, Ketones, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Receptors, Neurotransmitter, 3. Good health, MESH: tau Proteins, MESH: Cattle, medicine.anatomical_structure, Biochemistry, Molecular Medicine, Signal transduction, MESH: Models, Molecular, Protein Binding, MESH: Rats, Central nervous system, tau Proteins, In Vitro Techniques, Structure-Activity Relationship, 03 medical and health sciences, medicine, Animals, Humans, Structure–activity relationship, MESH: Protein Binding, Binding site, MESH: Mice, 030304 developmental biology, Binding Sites, MESH: Humans, MESH: Phosphorylation, 010405 organic chemistry, MESH: Central Nervous System Agents, MESH: Stereoisomerism, MESH: Cerebellum, Rats, 0104 chemical sciences, MESH: Binding Sites, Drug Design, Cattle, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Central Nervous System Agents
Abstract

Development of kinase-targeted therapies for central nervous system (CNS) diseases is a great challenge. Glycogen synthase kinase 3 (GSK-3) offers a great potential for severe CNS unmet diseases, being one of the inhibitors on clinical trials for different tauopathies. Following our hypothesis based on the enhanced reactivity of residue Cys199 in the binding site of GSK-3, we examine here the suitability of phenylhalomethylketones as irreversible inhibitors. Our data confirm that the halomethylketone unit is essential for the inhibitory activity. Moreover, addition of the halomethylketone moiety to reversible inhibitors turned them into irreversible inhibitors with IC50 values in the nanomolar range. Overall, the results point out that these compounds might be useful pharmacological tools to explore physiological and pathological processes related to signaling pathways regulated by GSK-3 opening new avenues for the discovery of novel GSK-3 inhibitors. © 2011 American Chemical Society.

Published
2011

23. CSF biomarkers in posterior cortical atrophy

Author

Maïté Formaglio, B. Croisile, Armand Perret-Liaudet, M. Salzmann, Aline Dorey, H. Mollion, Yannick Tholance, Isabelle Quadrio, Pierre Krolak-Salmon, M. Bataillard, Alain Vighetto, Olivier Moreaud, Olivier Rouaud, M.-H. Coste, J. Seguin, Catherine Thomas-Antérion, Laboratoire de Neurochimie, Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génie des procédés - environnement - agroalimentaire (GEPEA), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN)-Institut Universitaire de Technologie - Nantes (IUT Nantes), Université de Nantes (UN)-Institut Universitaire de Technologie Saint-Nazaire (IUT Saint-Nazaire), Université de Nantes (UN)-Institut Universitaire de Technologie - La Roche-sur-Yon (IUT La Roche-sur-Yon), Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Université Bretagne Loire (UBL), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Psychologie et NeuroCognition (LPNC), Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Unité de Neuropsychologie, CHU Grenoble, Atmospheric Chemistry Department [MPIC], Max Planck Institute for Chemistry (MPIC), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], and Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS)

Subjects
Pathology, medicine.medical_specialty, MESH: Atrophy, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Atrophy, medicine, Dementia, MESH: Syndrome, Neuropsychological assessment, Prospective cohort study, 030304 developmental biology, MESH: Aged, 0303 health sciences, MESH: Humans, MESH: Middle Aged, medicine.diagnostic_test, MESH: Biological Markers, Posterior cortical atrophy, MESH: Neuropsychological Tests, medicine.disease, MESH: Prospective Studies, MESH: Amyloid beta-Peptides, MESH: Cerebral Cortex, MESH: Dementia, MESH: Male, 3. Good health, MESH: tau Proteins, MESH: Vision Disorders, Biomarker (medicine), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Alzheimer's disease, Psychology, MESH: Female, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract

International audience; OBJECTIVE: To describe CSF biomarker profiles in posterior cortical atrophy (PCA), which induces high-order visual deficits often associated with Alzheimer disease (AD) pathology, and relate these findings to clinical and neuropsychological assessment. METHODS: This prospective observational study included 22 patients with PCA who underwent CSF biomarker analysis of total tau (t-tau), phosphorylated tau on amino acid 181 (p-tau181), and amyloid β (Aβ(42)). At group level, the CSF profiles of patients with PCA were compared to those of patients with typical AD and patients with other dementia (OD). Individually, the clinical presentation of patients with PCA was correlated to their CSF profile to assess the predictability of clinical features for diagnosis of underlying AD pathology. RESULTS: At group level, the PCA biomarker profile was not different from that of the AD group, but very different from that of the OD group (p < 0.001). More than 90% of patients with PCA had CSF profiles consistent with AD. All patients with PCA with either isolated higher-order visual deficit (n = 8) or visual deficit associated with memory impairment (n = 11) had CSF profiles consistent with AD. Only one of the 3 patients with PCA with asymmetric motor signs fulfilled biological CSF criteria for AD. CONCLUSIONS: PCA syndrome is usually associated with CSF biomarkers suggestive of AD, as shown by previous neuropathologic studies. This does not apply in case of motor signs suggesting associated corticobasal syndrome. CSF biomarkers help to discriminate AD from non-AD processes associated with this condition.

Published
2011

24. Protein aggregation in the aging retina

Author

Pierre-Olivier Fernagut, François Tison, François Léger, Erwan Bezard, Sandy Léoni, Anne Vital, Claude Vital, Marie-Hélène Canron, Institut des Maladies Neurodégénératives [Bordeaux] ( IMN ), Université de Bordeaux ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Pluridisciplinaire Textes et Cultures ( CPTC ), Université de Bourgogne ( UB ), Centre de Recherche sur la Matière Divisée ( CRMD ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Groupe de recherches sur l'énergétique des milieux ionisés ( GREMI ), Centre National de la Recherche Scientifique ( CNRS ) -Université d'Orléans ( UO ), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre Pluridisciplinaire Textes et Cultures (CPTC), Université de Bourgogne (UB), Centre de Recherche sur la Matière Divisée (CRMD), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)

Subjects
Male, Aging, [SDV]Life Sciences [q-bio], MESH : Aged, Protein aggregation, 0302 clinical medicine, MESH: Aged, 80 and over, Ubiquitin, MESH: Eye Proteins, MESH: Aging, MESH : Female, MESH: Nerve Tissue Proteins, MESH : Nerve Tissue Proteins, MESH : Ubiquitin, MESH: Aged, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, biology, MESH: Retina, MESH : alpha-Synuclein, General Medicine, Middle Aged, Cell biology, MESH: tau Proteins, medicine.anatomical_structure, Neurology, Biochemistry, Inner nuclear layer, alpha-Synuclein, Female, MESH: Ubiquitin, MESH : Male, Tau protein, MESH : tau Proteins, Nerve Tissue Proteins, tau Proteins, Drusen, Retina, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH : Eye Proteins, MESH: alpha-Synuclein, mental disorders, medicine, Humans, MESH : Middle Aged, MESH : Aged, 80 and over, Eye Proteins, 030304 developmental biology, Aged, Retinal pigment epithelium, MESH: Humans, [ SDV ] Life Sciences [q-bio], MESH : Humans, Colocalization, MESH : Retina, medicine.disease, MESH: Male, MESH : Aging, biology.protein, Neurology (clinical), sense organs, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; The age-related altered expression of neuron-related proteins as seen in other regions of the central nervous system is expected in the aging retina. Using immunohistochemical techniques, we characterized the distribution and aggregation of tau, βA4-amyloid, α-synuclein, and ubiquitin in human retina obtained from 19 enucleated eyes of patients aged 49 to 87 years and correlated the findings with the ages. Using a phosphorylation-independent antibody, tau aggregates were observed within the cytoplasm of several photoreceptor cells, and there was a positive correlation between age and the number of tau-positive ganglionic cells. Tau deposits were immunonegative with a phosphorylation-dependent antibody. We did not observe βA4-amyloid in subretinal pigment epithelium deposits or in neuroepithelial layers. α-Synuclein and ubiquitin inclusions were found in the inner nuclear layer, and there was colocalization of these proteins. The proportion of patients displaying such α-synuclein and/or ubiquitin intracytoplasmic inclusions was significantly higher with aging. The presence of ubiquitin deposits within drusen was remarkable, but diffuse ubiquitin aggregates between the retinal pigment epithelium and Bruch membrane were also noticed. These results indicate that protein aggregation in the retina increases with aging and that tau, α-synuclein, and ubiquitin should be the subjects of future investigations.

Published
2010

25. NMR spectroscopy of the neuronal tau protein: normal function and implication in Alzheimer's disease

Author

Arnaud Leroy, Isabelle Huvent, Luc Buée, Isabelle Landrieu, Malika Hamdane, Guy Lippens, Caroline Smet-Nocca, Laziza Amniai, Jean-Michel Wieruszeski, Nathalie Sibille, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), 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 de Lille-Centre National de la Recherche Scientifique (CNRS), 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, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine

Subjects
Models, Molecular, Tau protein, MESH: Neurons, tau Proteins, Isomerase, Proteomics, Biochemistry, 03 medical and health sciences, Alzheimer Disease, MESH: Nuclear Magnetic Resonance, Biomolecular, Animals, Humans, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Phosphorylation, MESH: Protein Kinases, Nuclear Magnetic Resonance, Biomolecular, 030304 developmental biology, chemistry.chemical_classification, Neurons, 0303 health sciences, MESH: Humans, MESH: Phosphorylation, biology, Kinase, 030302 biochemistry & molecular biology, Nuclear magnetic resonance spectroscopy, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: tau Proteins, Amino acid, chemistry, PIN1, biology.protein, Protein Kinases, MESH: Alzheimer Disease, MESH: Models, Molecular
Abstract

International audience; NMR spectroscopy was used to explore the different aspects of the normal and pathological functions of tau, but proved challenging because the protein contains 441 amino acids and has poor signal dispersion. We have set out to dissect the phosphorylation patterns of tau in order to understand better its role in the aggregation process and microtubule-binding regulation. Our current knowledge on the functional consequences of specific phosphorylations is still limited, mainly because producing and assessing quantitatively phosphorylated tau samples is far from straightforward, even in vitro. We use NMR spectroscopy as a proteomics tool to characterize the phosphorylation patterns of tau, after in vitro phosphorylation by recombinant kinases. The phosphorylated tau can next be use for functional assays or interaction assays with phospho-dependent protein partners, such as the prolyl cis-trans isomerase Pin1.

Published
2010

26. Degenerative abnormalities in transgenic neocortical neuropeptide Y interneurons expressing tau-green fluorescent protein

Author

Tania Vitalis, Armelle Rancillac, Hélène Geoffroy, Isabelle Ferezou, Quentin Perrenoud, Jean Rossier, Jeanne Lainé, Laboratoire de Neurobiologie, Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Contract grant sponsor: French National Research Agency, Contract grant number: ANR-06-NEURO-033-01., Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249) (PdC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Rancillac, Armelle

Subjects
Male, Patch-Clamp Techniques, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV]Life Sciences [q-bio], Fluorescent Antibody Technique, Green fluorescent protein, MESH: Neurodegenerative Diseases, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: Microscopy, Immunoelectron, MESH: Reverse Transcriptase Polymerase Chain Reaction, Neuropeptide Y, MESH: Animals, Microscopy, Immunoelectron, MESH: Fluorescent Antibody Technique, 0303 health sciences, biology, LAMP1, Reverse Transcriptase Polymerase Chain Reaction, Neurodegenerative Diseases, patch-clamp, Neuropeptide Y receptor, MESH: Interneurons, humanities, Cell biology, MESH: tau Proteins, [SDV] Life Sciences [q-bio], MESH: Luminescent Proteins, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], thickenings and tauopathy, Cell type, MESH: Axons, MESH: Lysosome-Associated Membrane Glycoproteins, MESH: Mice, Transgenic, Transgene, Tau protein, Mice, Transgenic, tau Proteins, spheroids, In Vitro Techniques, MESH: Dendrites, scRT-PCR, MESH: Somatosensory Cortex, 03 medical and health sciences, Cellular and Molecular Neuroscience, Interneurons, omatosensory cortex, MESH: Mice, Inbred C57BL, Biocytin, mental disorders, MESH: Patch-Clamp Techniques, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, MESH: Lysine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Neuropeptide Y, MESH: Mice, 030304 developmental biology, Reporter gene, Lysine, fungi, Lysosome-Associated Membrane Glycoproteins, Dendrites, Somatosensory Cortex, Neurolucida reconstructions, Axons, MESH: Male, axonal swellings, Mice, Inbred C57BL, Luminescent Proteins, chemistry, nervous system, biology.protein, bacterial artificial chromosome, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; The introduction of a reporter gene into bacterial artificial chromosome (BAC) constructs allows a rapid identification of the cell type expressing the gene of interest. Here we used BAC transgenic mice expressing a tau-sapphire green fluorescent protein (GFP) under the transcriptional control of the neuropeptide Y (NPY) genomic sequence to characterize morphological and electrophysiological properties of NPY-GFP interneurons of the mouse juvenile primary somatosensory cortex. Electrophysiological whole-cell recordings and biocytin injections were performed to allow the morphological reconstruction of the recorded neurons in three dimensions. Ninety-six recorded NPY-GFP interneurons were compared with 39 wild-type (WT) NPY interneurons, from which 23 and 19 were reconstructed, respectively. We observed that 91% of the reconstructed NPY-GFP interneurons had developed an atypical axonal swelling from which emerge numerous ramifications. These abnormalities were very heterogeneous in shape and size. They were immunoreactive for the microtubule-associated protein tau and the lysosomal-associated membrane protein 1 (LAMP1). Moreover, an electron microscopic analysis revealed the accumulation of numerous autophagic and lysosomal vacuoles in swollen axons. Morphological analyses of NPY-GFP interneurons also indicated that their somata were smaller, their entire dendritic tree was thickened and presented a restricted spatial distribution in comparison with WT NPY interneurons. Finally, the morphological defects observed in NPY-GFP interneurons appeared to be associated with alterations of their electrophysiological intrinsic properties. Altogether, these results demonstrate that NPY-GFP interneurons developed dystrophic axonal swellings and severe morphological and electrophysiological defects that could be due to the overexpression of tau-coupled reporter constructs.

Published
2010

27. The thioredoxin-like protein rod-derived cone viability factor (RdCVFL) interacts with TAU and inhibits its phosphorylation in the retina

Author

François Delalande, Olivier Poch, Therese Cronin, Géraldine Millet-Puel, Ram Fridlich, Alain Van Dorsselaer, Arne Holmgren, Céline Jaillard, Jun Lu, Ludivine Perrocheau, Thierry Léveillard, José-Alain Sahel, Marie-Laure Niepon, Laetitia Poidevin, Laboratoire de Physiopathologie Cellulaire et Moleculaire de la Retine, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Biochemistry and Biophysics, karolinska institute-Medical Nobel Institute for Biochemistry, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, 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), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-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), Peney, Maité, and Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Retinal degeneration, MESH: Protein Isoforms, Biochemistry, MESH: Mice, Knockout, Analytical Chemistry, Mice, Thioredoxins, 0302 clinical medicine, MESH: Thioredoxins, MESH: Eye Proteins, Tandem Mass Spectrometry, Protein Isoforms, MESH: Animals, Phosphorylation, Mice, Knockout, Mice, Inbred BALB C, 0303 health sciences, MESH: Oxidative Stress, biology, MESH: Retina, 3. Good health, MESH: tau Proteins, Signal transduction, Thioredoxin, Protein Binding, Programmed cell death, Tau protein, MESH: Mice, Inbred BALB C, tau Proteins, Retina, Cell Line, 03 medical and health sciences, Retinitis pigmentosa, medicine, Animals, Humans, MESH: Protein Binding, Eye Proteins, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH: Phosphorylation, Research, Alternative splicing, MESH: Tandem Mass Spectrometry, medicine.disease, Molecular biology, MESH: Cell Line, Oxidative Stress, biology.protein, sense organs, MESH: Chromatography, Liquid, 030217 neurology & neurosurgery, Chromatography, Liquid
Abstract

International audience; Rod-derived cone viability factor (RdCVF) is produced by the Nxnl1 gene that codes for a second polypeptide, RdCVFL, by alternative splicing. Although the role of RdCVF in promoting cone survival has been described, the implication of RdCVFL, a putative thioredoxin enzyme, in the protection of photoreceptors is presently unknown. Using a proteomics approach we identified 90 proteins interacting with RdCVFL including the microtubule-binding protein TAU. We demonstrate that the level of phosphorylation of TAU is increased in the retina of the Nxnl1(-/-) mice as it is hyperphosphorylated in the brain of patients suffering from Alzheimer disease, presumably in some cases through oxidative stress. Using a cell-based assay, we show that RdCVFL inhibits TAU phosphorylation. In vitro, RdCVFL protects TAU from oxidative damage. Photooxidative stress is implicated in retinal degeneration, particularly in retinitis pigmentosa, where it is considered to be a contributor to secondary cone death. The functional interaction between RdCVFL and TAU described here is the first characterization of the RdCVFL signaling pathway involved in neuronal cell death mediated by oxidative stress.

Published
2009

28. Intrafamilial diversity of phenotype associated with app duplication

Author

I. Guyant-Marechal, Didier Hannequin, Annie Laquerrière, Thierry Frebourg, Anne Rovelet-Lecrux, Gabriel Viennet, Lucien Rumbach, Eric Berger, Dominique Campion, Laboratoire de modélisation en mécanique (LMM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Estrogènes, Expression génique et pathologies du Système Nerveux Central - UFC (E2SNC / ESTROGENES), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Proband, Pediatrics, Neurology, MESH: Cerebral Amyloid Angiopathy, MESH: Intermediate Filament Proteins, Neuropsychological Tests, Apraxia, Amyloid beta-Protein Precursor, Epilepsy, 0302 clinical medicine, Intermediate Filament Proteins, Gene Duplication, MESH: Amyloid beta-Protein Precursor, Medicine, MESH: Nerve Tissue Proteins, ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, MESH: Middle Aged, MESH: Gene Duplication, Neuropsychology, MESH: Neuropsychological Tests, Middle Aged, 3. Good health, MESH: tau Proteins, Phenotype, Cerebral amyloid angiopathy, Lewy Body Disease, medicine.medical_specialty, Nerve Tissue Proteins, tau Proteins, MESH: Phenotype, 03 medical and health sciences, Alzheimer Disease, mental disorders, Humans, Dementia, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: Lewy Body Disease, Family Health, MESH: Humans, business.industry, Dementia with Lewy bodies, medicine.disease, MESH: Male, Cerebral Amyloid Angiopathy, MESH: Family Health, Neurology (clinical), business, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract

Different APP locus duplications have been recently identified in rare families with autosomal dominant early onset Alzheimer disease (AD) and Aβ-related cerebral amyloid angiopathy (CAA).1–3 We report a novel family revealing a very large diversity of phenotype including dementia with Lewy bodies (DLB). ### Methods. Family members gave informed consent according to a protocol approved by the ethics committees of the CCPPRB Pitie-Salpetriere and Paris-Necker. Characterization of five patients, with two detailed neuropsychological evaluations, brain MRI of three patients, and one neuropathologic evaluation, were assessed. APP locus was analyzed by quantitative multiplex PCR of short fluorescent fragments (QMPSF) in three patients. Patients were considered affected if they had dementia, intracerebral hemorrhage (ICH), or epilepsy (e-Methods on the Neurology ® Web site at www.neurology.org). ### Results. The proband (II-1, figure e-1) developed bradykinesia, memory problems, and apraxia when she was 44 years old. She developed paranoid delusion with visual hallucinations at 50 years of age. The association with bilateral tremor, rigidity, and bradykinesia was suggestive of DLB. Several T2 lesions were noted on MRI. She died at 55 years of age. Patients I-2 and I-3 had progressive memory disturbances with behavioral changes suggestive of AD since they were 55 and 60 years of age. Patient II-3 had partial visual seizures at the age …

Published
2008

29. Inhibition of glycogen synthase kinase-3beta downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A

Author

Amandine Magnaudeix, Faraj Terro, Ludovic Martin, Françoise Esclaire, Catherine Yardin, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service d'Histologie, cytologie, cytogénétique, biologie cellulaire [CHU Limoges], CHU Limoges, Equipe de Recherche Médicale Appliquée (ERMA), and Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges

Subjects
Indoles, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, MESH: Okadaic Acid, Glycogen Synthase Kinase 3, 0302 clinical medicine, GSK-3, Oximes, MESH: Animals, Protein Phosphatase 2, Enzyme Inhibitors, Phosphorylation, Cells, Cultured, MESH: Glycogen Synthase Kinase 3, MESH: Indoles, Neurons, 0303 health sciences, biology, Chemistry, General Neuroscience, MESH: Protein Phosphatase 2, Calcineurin, Neurodegeneration, MESH: Lithium Chloride, MESH: Purines, MESH: Oximes, MESH: tau Proteins, MESH: Enzyme Inhibitors, MESH: Calcineurin, MESH: Cells, Cultured, MESH: Cyclin-Dependent Kinase 5, MESH: Rats, Tau protein, Blotting, Western, Calcineurin Inhibitors, tau Proteins, macromolecular substances, Tacrolimus, 03 medical and health sciences, MESH: Analysis of Variance, mental disorders, Okadaic Acid, medicine, MESH: Tacrolimus, Roscovitine, MESH: Blotting, Western, Animals, Rats, Wistar, Glycogen synthase, Molecular Biology, GSK3B, 030304 developmental biology, Analysis of Variance, Glycogen Synthase Kinase 3 beta, MESH: Phosphorylation, Cyclin-dependent kinase 5, Cyclin-Dependent Kinase 5, Protein phosphatase 2, MESH: Rats, Wistar, medicine.disease, Molecular biology, Rats, enzymes and coenzymes (carbohydrates), Purines, biology.protein, Neurology (clinical), Lithium Chloride, 030217 neurology & neurosurgery, Developmental Biology
Abstract

ERMA; International audience; In tauopathies such as Alzheimer's disease (AD), the molecular mechanisms of tau protein aggregation into neurofibrillary tangles (NFTs) and their contribution to neurodegeneration remain not understood. It was recently demonstrated that tau, regardless of its aggregation, might represent a key mediator of neurodegeneration. Therefore, reduction of tau levels might represent a mechanism of neuroprotection. Glycogen synthase kinase-3beta (GSK3beta) and protein phosphatase-2A (PP2A) are key enzymes involved in the regulation of tau phosphorylation, and have been suggested to be involved in the abnormal tau phosphorylation and aggregation in AD. Connections between PP2A and GSK3beta signaling have been reported. We have previously demonstrated that exposure of cultured cortical neurons to lithium decreased tau protein expression and provided neuroprotection against Abeta. Since lithium is not a specific inhibitor of GSK3beta (ID50=2.0 mM), whether or not the lithium-induced tau decrease involves GSK3beta remained to be determined. For that purpose, cultured cortical neurons were exposed to 6-bromo-indirubin-3'-oxime (6-BIO), a more selective and potent GSK3beta inhibitor (ID50=1.5 microM) or to lithium. Analysis of tau levels and phosphorylation by western-blot assays showed that lithium and 6-BIO dose-dependently decreased both tau protein levels and tau phosphorylation. Conversely, inhibition of cyclin-dependent kinase-5 (CDK5) by roscovitine decreased phosphorylated tau but failed to alter tau protein levels. These data indicate that GSK3beta might be selectively involved in the regulation of tau protein levels. Moreover, inhibition of PP2A by okadaic acid, but not that of PP2B (protein phosphatase-2B)/calcineurin by FK506, dose-dependently reversed lithium-induced tau decrease. These data indicate that GSK3beta regulates both tau phosphorylation and total tau levels through PP2A.

Published
2008

30. Lithium down-regulates tau in cultured cortical neurons: a possible mechanism of neuroprotection

Author

A. Rametti, Françoise Esclaire, Faraj Terro, Catherine Yardin, N. Cogné, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Equipe de Recherche Médicale Appliquée (ERMA), Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Lithium (medication), MESH: Neurons, Apoptosis, MESH: Lithium Compounds, MESH: Down-Regulation, MESH: Dose-Response Relationship, Drug, Glycogen Synthase Kinase 3, 0302 clinical medicine, Antimanic Agents, MESH: Animals, Cells, Cultured, MESH: Glycogen Synthase Kinase 3, Cerebral Cortex, Neurons, 0303 health sciences, biology, Chemistry, General Neuroscience, Neurodegeneration, Neurofibrillary Tangles, MESH: Antimanic Agents, MESH: Neuroprotective Agents, MESH: Amyloid beta-Peptides, MESH: tau Proteins, Neuroprotective Agents, medicine.anatomical_structure, Lithium Compounds, [SDV.IMM]Life Sciences [q-bio]/Immunology, Alzheimer's disease, medicine.drug, MESH: Cells, Cultured, Amyloid, MESH: Rats, Tau protein, Down-Regulation, tau Proteins, Neuroprotection, 03 medical and health sciences, Alzheimer Disease, mental disorders, medicine, Animals, RNA, Messenger, Rats, Wistar, GSK3B, 030304 developmental biology, MESH: RNA, Messenger, Amyloid beta-Peptides, Glycogen Synthase Kinase 3 beta, Dose-Response Relationship, Drug, MESH: Apoptosis, MESH: Rats, Wistar, medicine.disease, MESH: Cerebral Cortex, Rats, MESH: Cytoprotection, Cytoprotection, biology.protein, Neuron, Neuroscience, 030217 neurology & neurosurgery, MESH: Alzheimer Disease, MESH: Neurofibrillary Tangles
Abstract

ERMA; International audience; In tauopathies such as Alzheimer's disease (AD), the moleccular mechanisms of tau protein agregation into neurofibrillary tangles (NFTs) and their contribution to neurodegeneration are not fully understood. Recent studies indirectly demonstrated that tau, regardless of its aggregation, might represent a key mediator of neurodegeneration, especially that induced by the amyloid (Abeta) pathology. Lithium is a medication for bipolar mood disorders. Its therapeutic mechanism of action remains unclear, in part because of the large number of biochemical effects attributed to lithium. Since lithium directly inhibits glycogen synthase kinase-3beta (GSK3beta), a key enzyme involved in tau phosphorylation, it was suggested that the therapeutic use of lithium could be expanded from mood disorders to neurodegenerative conditions. Lithium has been also reported to protect cultured neurons against Abeta toxicity, and to prevent NFTs accumulation and cognitive impairments in transgenic models of tauopathies. However, the exact mechanism of neuroprotection provided by lithium remains unknown. Here, we show that exposure of cultured cortical neurons to lithium decreased tau protein levels. This decrease was not linked to the activation of proteolytic processes including calpains, caspases and proteasome or to neuronal loss, but was rather associated with a reduction in tau mRNA levels. Moreover, prior exposure to lithium, at concentrations effective in reducing tau protein levels, markedly reduced pre-aggregated Abeta-induced neuronal apoptosis. Our findings raise the possibility that lithium could exert its neuroprotective effect against Abeta toxicity through the downregulation of tau proteins and that, at least, by acting at the level of tau mRNA.

Published
2008

31. Derivation and cloning of a novel rhesus embryonic stem cell line stably expressing tau-green fluorescent protein

Author

Suzy Markossian, Pierre Savatier, C. Huissoud, Guillaume Marcy, Pascale Giroud, Henry Kennedy, Agnieszka Bernat, Vincent Leviel, Veronique Cortay, Florence Wianny, Colette Dehay, Dehay, Colette, Institut cellule souche et cerveau (U846 Inserm - UCBL1), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Gynécologie et Obstétrique [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Unité sous contrat plate-forme biotechnologique de cellules souches plate-forme PrimaStem, INSERM/AFM Cellules Souches Thérapeutiques grant n°4CS016F Région Rhône-Alpes (Emergence, n°0101681601 « Thématique prioritaire cellules souches », n°0301455301), Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (SBRI), and Université Claude Bernard Lyon 1 (UCBL)

Subjects
Cellular differentiation, Green fluorescent protein, 0302 clinical medicine, MESH: Alkaline Phosphatase, Genes, Reporter, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Animals, MESH: Embryonic Stem Cells, Neural cell, MESH: Zona Pellucida, MESH: Lentivirus, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Teratoma, Cell Differentiation, MESH: Teratoma, Cell cycle, 3. Good health, MESH: tau Proteins, Molecular Medicine, MESH: Stem Cell Transplantation, MESH: Cell Differentiation, Green Fluorescent Proteins, tau Proteins, Germ layer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Transfection, Article, Cell Line, MESH: Macaca mulatta, 03 medical and health sciences, MESH: Green Fluorescent Proteins, In vivo, Animals, Reporter, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Embryonic Stem Cells, Zona Pellucida, 030304 developmental biology, MESH: Transfection, Lentivirus, MESH: Genes, Reporter, Cell Biology, Alkaline Phosphatase, Embryonic stem cell, Molecular biology, Macaca mulatta, MESH: Cell Line, MESH: Blastocyst, Blastocyst, Genes, Cell culture, 030217 neurology & neurosurgery, Developmental Biology, Stem Cell Transplantation
Abstract

Embryonic stem cells (ESC) have the ability of indefinite self-renewal and multilineage differentiation, and they carry great potential in cell-based therapies. The rhesus macaque is the most relevant preclinical model for assessing the benefit, safety, and efficacy of ESC-based transplantations in the treatment of neurodegenerative diseases. In the case of neural cell grafting, tracing both the neurons and their axonal projections in vivo is essential for studying the integration of the grafted cells in the host brain. Tau-Green fluorescent protein (tau-GFP) is a powerful viable lineage tracer, allowing visualization of cell bodies, dendrites, and axons in exquisite detail. Here, we report the first rhesus monkey ESC line that ubiquitously and stably expresses tau-GFP. First, we derived a new line of rhesus monkey ESC (LYON-ES1) that show marker expression and cell cycle characteristics typical of primate ESCs. LYON-ES1 cells are pluripotent, giving rise to derivatives of the three germ layers in vitro and in vivo through teratoma formation. They retain all their undifferentiated characteristics and a normal karyotype after prolonged culture. Using lentiviral infection, we then generated a monkey ESC line stably expressing tau-GFP that retains all the characteristics of the parental wild-type line and is clonogenic. We show that neural precursors derived from the tau-GFP ESC line are multipotent and that their fate can be precisely mapped in vivo after grafting in the adult rat brain. Disclosure of potential conflicts of interest is found at the end of this article.

Published
2008

32. Progranulin null mutations in both sporadic and familial frontotemporal dementia

Author

Michèle Puel, Marleen Van den Broeck, Annie Laquerrière, Marc Cruts, Agnès Camuzat, Martine Vercelletto, Bernard-François Michel, Bruno Dubois, Mira Didic, Patrice Verpillat, Catherine Thomas-Antérion, Véronique Golfier, Alexis Brice, Didier Hannequin, Ilse Gijselinck, Tim De Pooter, Lucette Lacomblez, François Sellal, Dominique Campion, François Salachas, Isabelle Le Ber, Charles Duyckaerts, Christine Van Broeckhoven, Julie van der Zee, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Neurodegenerative Brain Diseases Group, University of Antwerp (UA)-Flanders Interuniversity Institute of Biotechnology, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Department of Genetics, University Hospital, Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Department of Neuropathology, Neuro-anatomie fonctionnelle du comportement et de ses troubles, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], 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), Département de Neurologie, CHU Saint-Etienne, Service de neurologie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte Marguerite, Service de neurologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Epilepsies, Lesions Cerebrales et Systemes Neuraux de la Cognition, Université de la Méditerranée - Aix-Marseille 2-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) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Antwerpen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-06-MRAR-005-01, ANR Maladies Rares DFT-MND, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Université de Rennes (UR), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], and French Research Network on FTD/FTD-MND

Subjects
Male, medicine.disease_cause, Apraxia, 0302 clinical medicine, Progranulins, MESH: Aged, 80 and over, MESH: Genetic Screening, MESH: Codon, Nonsense, Family history, Genetics (clinical), Genetics, Aged, 80 and over, MESH: Aged, 0303 health sciences, Mutation, MESH: Middle Aged, medicine.diagnostic_test, Parkinsonism, Middle Aged, Penetrance, MESH: Dementia, 3. Good health, Pedigree, MESH: tau Proteins, Phenotype, Codon, Nonsense, Intercellular Signaling Peptides and Proteins, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Frontotemporal dementia, MESH: Pedigree, tau Proteins, Biology, MESH: Phenotype, 03 medical and health sciences, mental disorders, medicine, Dementia, Humans, Genetic Testing, MESH: Intercellular Signaling Peptides and Proteins, 030304 developmental biology, Genetic testing, Aged, MESH: Humans, nutritional and metabolic diseases, medicine.disease, MESH: Male, nervous system diseases, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD.

Published
2007

33. Genetic mouse models of Alzheimer's disease

Author

Declan M. McLoughlin, Yann S. Mineur, Wim E. Crusio, Frans Sluyter, Neurosciences cognitives (NC), and Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Mice, Transgenic, Mice, Transgenic, tau Proteins, Disease, Biology, Article, lcsh:RC321-571, 03 medical and health sciences, Mice, 0302 clinical medicine, Alzheimer Disease, Genetic model, Endopeptidases, medicine, Animals, Aspartic Acid Endopeptidases, Humans, MESH: Animals, MESH: Endopeptidases, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, MESH: Mice, 030304 developmental biology, 0303 health sciences, MESH: Humans, MESH: Aspartic Endopeptidases, medicine.disease, Mice transgenic, MESH: tau Proteins, Disease Models, Animal, Neurology, MESH: Amyloid Precursor Protein Secretases, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Alzheimer's disease, Amyloid Precursor Protein Secretases, MESH: Disease Models, Animal, Neuroscience, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract

International audience; In the current minireview, we focus on genetic mouse models of Alzheimer's disease (AD). Because various excellent, up-to-date reviews, special issues, and reliable websites are already dedicated to the genetics of Alzheimer's disease in general and of animal models in particular, this review is not meant to be comprehensive. Rather, we aim to steer the Alzheimer's novice through the recent mouse literature on AD. Special attention will be paid to genetic models that have been tested behaviorally.

Published
2005

34. Association of polymorphisms in the Tau and Saitohin genes with Parkinson's disease

Author

Jacqueline Clavel, Christophe Tzourio, P. Amouyel, Jean-Sébastien Vidal, C Levecque, Marie-Christine Chartier-Harlin, Annick Alpérovitch, Alexis Elbaz, Epidémiologie des maladies chroniques: impact des intéractions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Recherches épidémiologiques en neurologie et psychopathologie, Institut National de la Santé et de la Recherche Médicale (INSERM), Recherches épidémiologiques et statistiques sur l'environnement et la santé., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), The study was supported by the INSERM, the Institut Pasteur de Lille, the MSA, and the French Ministry of the Environment. CL is a recipient of the Ministère de la Recherche et de la Technologie., We thank all the MSA (Mutualité Sociale Agricole) physicians who interviewed the participants and the MSA employees who helped with the coordination of the study. Drs David Gervais and Lamia Benslamia participated in the examination of Parkinson’s disease patients. Mrs Chantal Cordelier and Drs Carline Amiel, Frédérique Brunner, and Jean-Philippe Galanaud helped with the assessment of exposure to pesticides. Dr Safia Zenagui participated in the coordination of the study. We thank Prakash Rucktooa, Aurélie Melchior, Xavier Hermant, and Vincent Mouroux for their technical assistance., Service de neurologie [CHU Saint-Antoine], and Secretariat, U754

Subjects
Male, Candidate gene, Parkinson's disease, Short Report, tau Proteins, Locus (genetics), Biology, 03 medical and health sciences, 0302 clinical medicine, Degenerative disease, MESH: Polymorphism, Genetic, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, Allele, Aged, 030304 developmental biology, Genetics, MESH: Aged, 0303 health sciences, Polymorphism, Genetic, MESH: Humans, MESH: Middle Aged, Haplotype, Case-control study, MESH: Genetic Predisposition to Disease, Parkinson Disease, Odds ratio, MESH: Haplotypes, Middle Aged, medicine.disease, MESH: Case-Control Studies, MESH: Odds Ratio, MESH: Male, MESH: tau Proteins, Psychiatry and Mental health, Haplotypes, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Female, Surgery, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), MESH: Female, 030217 neurology & neurosurgery, MESH: Parkinson Disease
Abstract

International audience; BACKGROUND: The Saitohin gene has recently been identified in intron 9 of the Tau gene. Because an association between Parkinson's disease and Tau has been described, Saitohin represents a candidate gene for Parkinson's disease. OBJECTIVE: To test these two genes for their association with Parkinson's disease in a large community based case-control study. RESULTS: Cases (n = 208) were more often homozygotes for the Tau H1 haplotype than controls (n = 483; odds ratio (OR) = 1.71 (95% confidence interval, 1.20 to 2.43); p = 0.003), and the saitohin Q allele was in complete linkage disequilibrium with the H1 haplotype. This association was stronger among cases with Parkinson's disease onset below 65 years (< or =65 years: OR = 2.52 (1.49 to 4.25); p65 years: OR = 1.20 (0.73 to 1.98); p

Published
2004

35. Pathfinding of Corticothalamic Axons Relies on a Rendezvous with Thalamic Projections

Author

Sophie Chauvet, Marie Deck, Michio Yoshida, Caroline Mailhes, Fanny Mann, Elizabeth A. Grove, Mathieu Niquille, Yutaka Yoshida, Cécile Lebrand, Maryama Keita, Ludmilla Lokmane, Sonia Garel, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Department of Cellular Biology and Morphology, Université de Lausanne = University of Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne (UNIL), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris

Subjects
Nervous system, Thyroid Nuclear Factor 1, MESH: Membrane Glycoproteins, Semaphorins, Mice, 0302 clinical medicine, Molecular level, Thalamus, Neural Pathways, MESH: Gene Expression Regulation, Developmental, MESH: Animals, MESH: Nerve Tissue Proteins, Cerebral Cortex, MESH: Thalamus, 0303 health sciences, Neocortex, Membrane Glycoproteins, General Neuroscience, Age Factors, Intracellular Signaling Peptides and Proteins, Gene Expression Regulation, Developmental, Nuclear Proteins, MESH: Transcription Factors, Animals, Axons/physiology, Body Patterning/genetics, Calcium-Binding Protein, Vitamin D-Dependent/metabolism, Cerebral Cortex/cytology, Cerebral Cortex/physiology, Contactin 2/metabolism, DNA-Binding Proteins/metabolism, Embryo, Mammalian, Gene Expression Regulation, Developmental/genetics, Glycoproteins/genetics, Homeodomain Proteins/genetics, Leukocyte L1 Antigen Complex/metabolism, Luminescent Proteins/genetics, Luminescent Proteins/metabolism, Membrane Glycoproteins/genetics, Membrane Proteins/genetics, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins/genetics, Nerve Tissue Proteins/metabolism, Neural Pathways/physiology, Nuclear Proteins/metabolism, POU Domain Factors/genetics, Repressor Proteins/metabolism, Thalamus/cytology, Thalamus/physiology, Transcription Factors/genetics, Transcription Factors/metabolism, Tumor Suppressor Proteins/metabolism, Wnt3A Protein/genetics, tau Proteins/genetics, MESH: tau Proteins, DNA-Binding Proteins, medicine.anatomical_structure, Cerebral cortex, MESH: Repressor Proteins, Calbindin 2, MESH: Contactin 2, MESH: Luminescent Proteins, MESH: Membrane Proteins, Pathfinding, Psychology, MESH: Body Patterning, MESH: Axons, Cortical neuron, MESH: Mice, Transgenic, Neuroscience(all), MESH: Glycoproteins, Nerve Tissue Proteins, tau Proteins, MESH: POU Domain Factors, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Waiting period, Article, 03 medical and health sciences, S100 Calcium Binding Protein G, MESH: Leukocyte L1 Antigen Complex, MESH: Mice, Inbred C57BL, Wnt3A Protein, MESH: Homeodomain Proteins, medicine, Contactin 2, MESH: Tumor Suppressor Proteins, MESH: Wnt3A Protein, MESH: Mice, 030304 developmental biology, Body Patterning, Glycoproteins, Homeodomain Proteins, MESH: Age Factors, Tumor Suppressor Proteins, MESH: Neural Pathways, MESH: Calcium-Binding Protein, Vitamin D-Dependent, MESH: Embryo, Mammalian, Membrane Proteins, Axons, MESH: Cerebral Cortex, Repressor Proteins, Cytoskeletal Proteins, Luminescent Proteins, nervous system, POU Domain Factors, T-Box Domain Proteins, Neuroscience, Leukocyte L1 Antigen Complex, MESH: Nuclear Proteins, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Transcription Factors
Abstract

International audience; Major outputs of the neocortex are conveyed by corticothalamic axons (CTAs), which form reciprocal connections with thalamocortical axons, and corticosubcerebral axons (CSAs) headed to more caudal parts of the nervous system. Previous findings establish that transcriptional programs define cortical neuron identity and suggest that CTAs and thalamic axons may guide each other, but the mechanisms governing CTA versus CSA pathfinding remain elusive. Here, we show that thalamocortical axons are required to guide pioneer CTAs away from a default CSA-like trajectory. This process relies on a hold in the progression of cortical axons, or waiting period, during which thalamic projections navigate toward cortical axons. At the molecular level, Sema3E/PlexinD1 signaling in pioneer cortical neurons mediates a "waiting signal" required to orchestrate the mandatory meeting with reciprocal thalamic axons. Our study reveals that temporal control of axonal progression contributes to spatial pathfinding of cortical projections and opens perspectives on brain wiring.

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36. Studying Posttranslational Modifications by In-Cell NMR

Author

Isabelle Landrieu, Xavier Hanoulle, Guy Lippens, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
Magnetic Resonance Spectroscopy, Clinical Biochemistry, Intracellular Space, tau Proteins, MESH: Casein Kinase II, 01 natural sciences, Biochemistry, 03 medical and health sciences, Drug Discovery, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylation, Casein Kinase II, Molecular Biology, 030304 developmental biology, Pharmacology, 0303 health sciences, MESH: Humans, MESH: Phosphorylation, 010405 organic chemistry, Chemistry, MESH: Magnetic Resonance Spectroscopy, General Medicine, Nuclear magnetic resonance spectroscopy, 0104 chemical sciences, MESH: tau Proteins, MESH: Protein Processing, Post-Translational, Biophysics, Molecular Medicine, MESH: Intracellular Space, Protein Processing, Post-Translational
Abstract

Functional in vivo investigation of posttranslational modifications is a problem that a number of analytical techniques are trying to tackle. Below, we briefly discuss the breakthroughs and challenges in placing NMR spectroscopy on the map, as illustrated by a recent report by Selenko et al. (2008).

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