40 results on '"Bégard S"'
Search Results
2. Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors
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Lécolle, K, Bégard, S, Caillierez, R, Demeyer, D, Grellier, E, Loyens, A, Csaba, Z, Beauvillain, J C, D'Halluin, J C, Baroncini, M, Lejeune, J P, Sharif, A, Prévot, V, Dournaud, P, Buée, L, and Colin, M
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- 2013
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3. Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors
- Author
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Lécolle, K, primary, Bégard, S, additional, Caillierez, R, additional, Demeyer, D, additional, Grellier, E, additional, Loyens, A, additional, Csaba, Z, additional, Beauvillain, J C, additional, D'Halluin, J C, additional, Baroncini, M, additional, Lejeune, J P, additional, Sharif, A, additional, Prévot, V, additional, Dournaud, P, additional, Buée, L, additional, and Colin, M, additional
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- 2012
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4. O1-2 Récepteurs à la somatostatine : Une cible thérapeutique pour un transfert de gène spécifique dans le cerveau ?
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Lécolle, K., primary, Bégard, S., additional, Caillierez, R., additional, Grellier, E., additional, Grosjean, M.-E., additional, Blum, D., additional, Loyens, A., additional, Beauvillain, J.-C., additional, D’Halluin, J.-C., additional, Buée, L., additional, and Colin, M., additional
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- 2009
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5. P1-10 The prolyl isomerase PIN1 modulates oxydative stress-induced dephosphorylation of tau in neurons
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Galas, M.C., primary, Dourlen, P., additional, Bégard, S., additional, Vandesquille, M., additional, Hamdame, M., additional, and Buée, L., additional
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- 2005
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6. C2-4 La protéine microtubulaire Tau : le ying et le yang des tauopathies
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Hamdane, M., primary, Bretteville, A., additional, Ando, K., additional, Dourlen, P., additional, Schindowski, K., additional, Kerdraon, O., additional, Bégard, S., additional, Schraen-Mashke, S., additional, Caillet-Boudin, M.L., additional, Sergeant, N., additional, Delacourte, A., additional, Galas, M.C., additional, Maurage, C.A., additional, and Buée, L., additional
- Published
- 2005
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7. Abnormal Tau phosphorylation of the Alzheimer-type also occurs during mitosis.
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Delobel, P., Flament, S., Hamdane, M., Mailliot, C., Sambo, A-V., Bégard, S., Sergeant, N., Delacourte, A., Vilain, J-P., and Buée, L.
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ALZHEIMER'S disease ,MITOSIS ,PHOSPHORYLATION - Abstract
In Alzheimer's disease, neurofibrillary degeneration results from the aggregation of abnormally phosphorylated Tau proteins into filaments and it may be related to the reactivation of mitotic mechanisms. In order to investigate the link between Tau phosphorylation and mitosis, Xenopus laevis oocytes in which most of the M-phase regulators have been discovered were used as a cell model. The human Tau isoform htau412 (2+3–10+) was microinjected into prophase I oocytes that were then stimulated by progesterone that activate cyclin-dependent kinase pathways. Hyperphosphorylation of the Tau isoform, which is characterized by a decrease of its electrophoretic mobility and its labelling by a number of phosphorylation-dependent antibodies, was observed at the time of germinal vesicle breakdown. Surprisingly, Tau immunoreactivity, considered as typical of Alzheimer's pathology (AT100 and phospho-Ser422), was observed in meiosis II. Because meiosis II is considered as a mitosis-like phase, we investigated if our observation was also relevant to a neurone-like model. Abnormal Tau phosphorylation was detected in mitotic human neuroblastoma SY5Y cells overexpressing Tau. Regarding AT100-immunoreactivity and phospho-Ser422, we suggest that phosphatase 2A inhibition and a phosphorylation combination of mitotic kinases may lead to this Alzheimer-type phosphorylation. Our results not only demonstrate the involvement of mitotic kinases in Alzheimer-type Tau phosphorylation but also indicate that Xenopus oocyte could be a useful model to identify the kinases involved in this process. [ABSTRACT FROM AUTHOR]
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- 2002
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8. P1-049: Alzheimer-type neurofibrillary lesions and neurofilamentous inclusions are cell-type specific in transgenic mice expressing mutated tau proteins G272V/P301S
- Author
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Leroy, Karelle, Authelet, Michele, Schindowski, Katharina, Bretteville, Alexis, Dedecker, Robert, Zehra, Yilmaz, Gilissen, Emmanuel, Begard, S., Hamdane, Malika, Boom, Alain, Buee, Luc, and Brion, Jean-Pierre
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- 2006
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9. [Tau story: from frontotemporal dementia to other tauopathies]
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Luc BUEE, Hamdane M, Delobel P, Av, Sambo, Bégard S, Ghestem A, Sergeant N, and Delacourte A
10. Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice.
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Gomez-Murcia V, Launay A, Carvalho K, Burgard A, Meriaux C, Caillierez R, Eddarkaoui S, Kilinc D, Siedlecki-Wullich D, Besegher M, Bégard S, Thiroux B, Jung M, Nebie O, Wisztorski M, Déglon N, Montmasson C, Bemelmans AP, Hamdane M, Lebouvier T, Vieau D, Fournier I, Buee L, Lévi S, Lopes LV, Boutillier AL, Faivre E, and Blum D
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- Animals, Mice, Hippocampus metabolism, Hippocampus pathology, Presenilin-1 genetics, Disease Models, Animal, Plaque, Amyloid pathology, Plaque, Amyloid metabolism, Male, Mice, Inbred C57BL, Memory Disorders metabolism, Memory Disorders genetics, Memory Disorders pathology, Receptor, Adenosine A2A metabolism, Receptor, Adenosine A2A genetics, Synapses metabolism, Synapses pathology, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Mice, Transgenic, Neurons metabolism, Neurons pathology, Alzheimer Disease metabolism, Alzheimer Disease pathology, Alzheimer Disease genetics
- Abstract
Early pathological upregulation of adenosine A2A receptors (A2ARs), one of the caffeine targets, by neurons is thought to be involved in the development of synaptic and memory deficits in Alzheimer's disease (AD) but mechanisms remain ill-defined. To tackle this question, we promoted a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice developing AD-like amyloidogenesis. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioural changes were not linked to major change in the development of amyloid pathology but rather associated with increased phosphorylated tau at neuritic plaques. Moreover, proteomic and transcriptomic analyses coupled with quantitative immunofluorescence studies indicated that neuronal upregulation of the receptor promoted both neuronal and non-neuronal autonomous alterations, i.e. enhanced neuroinflammatory response but also loss of excitatory synapses and impaired neuronal mitochondrial function, presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction, as seen in the brain of patients, contributes to amyloid-related pathogenesis and underscores the potential of A2AR as a relevant therapeutic target for mitigating cognitive impairments in this neurodegenerative disorder., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2024
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11. A selection and optimization strategy for single-domain antibodies targeting the PHF6 linear peptide within the tau intrinsically disordered protein.
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Mortelecque J, Zejneli O, Bégard S, Simões MC, ElHajjar L, Nguyen M, Cantrelle FX, Hanoulle X, Rain JC, Colin M, Gomes CM, Buée L, Landrieu I, Danis C, and Dupré E
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- Humans, Epitopes chemistry, Epitopes immunology, Peptides chemistry, Peptides immunology, Intrinsically Disordered Proteins chemistry, Intrinsically Disordered Proteins immunology, Single-Domain Antibodies chemistry, Single-Domain Antibodies genetics, Single-Domain Antibodies immunology, tau Proteins chemistry, tau Proteins immunology
- Abstract
The use of variable domain of the heavy-chain of the heavy-chain-only antibodies (VHHs) as disease-modifying biomolecules in neurodegenerative disorders holds promises, including targeting of aggregation-sensitive proteins. Exploitation of their clinical values depends however on the capacity to deliver VHHs with optimal physico-chemical properties for their specific context of use. We described previously a VHH with high therapeutic potential in a family of neurodegenerative diseases called tauopathies. The activity of this promising parent VHH named Z70 relies on its binding within the central region of the tau protein. Accordingly, we carried out random mutagenesis followed by yeast two-hybrid screening to obtain optimized variants. The VHHs selected from this initial screen targeted the same epitope as VHH Z70 as shown using NMR spectroscopy and had indeed improved binding affinities according to dissociation constant values obtained by surface plasmon resonance spectroscopy. The improved affinities can be partially rationalized based on three-dimensional structures and NMR data of three complexes consisting of an optimized VHH and a peptide containing the tau epitope. Interestingly, the ability of the VHH variants to inhibit tau aggregation and seeding could not be predicted from their affinity alone. We indeed showed that the in vitro and in cellulo VHH stabilities are other limiting key factors to their efficacy. Our results demonstrate that only a complete pipeline of experiments, here described, permits a rational selection of optimized VHH variants, resulting in the selection of VHH variants with higher affinities and/or acting against tau seeding in cell models., Competing Interests: Conflict of interests J.-C. R. is the CEO of Hybrigenic services. Part of the work is included in patent WO2020120644 NEW ANTI TAU SINGLE DOMAIN ANTIBODY L. I., B. L., D. E., D. C., R. J.-C., and A. A. The other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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12. Integration of Microfluidic Devices with Microelectrode Arrays to Functionally Assay Amyloid-β-Induced Synaptotoxicity.
- Author
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Lefebvre C, Vreulx AC, Dumortier C, Bégard S, Gelle C, Siedlecki-Wullich D, Colin M, Kilinc D, and Halliez S
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- Mice, Animals, Humans, Microelectrodes, Amyloid beta-Peptides genetics, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides metabolism, Lab-On-A-Chip Devices, Neurodegenerative Diseases, Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology
- Abstract
Alzheimer's disease (AD) is a neurodegenerative disease and the most frequent cause of dementia. It is characterized by the accumulation in the brain of two pathological protein aggregates: amyloid-β peptides (Aβ) and abnormally phosphorylated tau. The progressive cognitive decline observed in patients strongly correlates with the synaptic loss. Many lines of evidence suggest that soluble forms of Aβ accumulate into the brain where they cause synapse degeneration. Stopping their spreading and/or targeting the pathophysiological mechanisms leading to synaptic loss would logically be beneficial for the patients. However, we are still far from understanding these processes. Our objective was therefore to develop a versatile model to assay and study Aβ-induced synaptotoxicity. We integrated a microfluidic device that physically isolates synapses from presynaptic and postsynaptic neurons with a microelectrode array. We seeded mouse primary cortical cells in the presynaptic and postsynaptic chambers. After functional synapses have formed in the synaptic chamber, we exposed them to concentrated conditioned media from cell lines overexpressing the wild-type or mutated amyloid precursor protein and thus secreting different levels of Aβ. We recorded the neuronal activity before and after exposition to Aβ and quantified Aβ's effects on the connectivity between presynaptic and postsynaptic neurons. We observed that the application of Aβ on the synapses for 48 h strongly decreased the interchamber connectivity without significantly affecting the neuronal activity in the presynaptic or postsynaptic chambers. Thus, through this model, we are able to functionally assay the impact of Aβ peptides (or other molecules) on synaptic connectivity and to use the latter as a proxy to study Aβ-induced synaptotoxicity. Moreover, since the presynaptic, postsynaptic, and synaptic chambers can be individually targeted, our assay provides a powerful tool to evaluate the involvement of candidate genes in synaptic vulnerability and/or test therapeutic strategies for AD.
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- 2024
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13. Tau promotes oxidative stress-associated cycling neurons in S phase as a pro-survival mechanism: Possible implication for Alzheimer's disease.
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Denechaud M, Geurs S, Comptdaer T, Bégard S, Garcia-Núñez A, Pechereau LA, Bouillet T, Vermeiren Y, De Deyn PP, Perbet R, Deramecourt V, Maurage CA, Vanderhaegen M, Vanuytven S, Lefebvre B, Bogaert E, Déglon N, Voet T, Colin M, Buée L, Dermaut B, and Galas MC
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- Humans, Mice, Animals, tau Proteins metabolism, S Phase, Phosphorylation, Oxidative Stress, Neurons metabolism, Amyloid beta-Peptides metabolism, Alzheimer Disease metabolism
- Abstract
Multiple lines of evidence have linked oxidative stress, tau pathology and neuronal cell cycle re-activation to Alzheimer's disease (AD). While a prevailing idea is that oxidative stress-induced neuronal cell cycle reactivation acts as an upstream trigger for pathological tau phosphorylation, others have identified tau as an inducer of cell cycle abnormalities in both mitotic and postmitotic conditions. In addition, nuclear hypophosphorylated tau has been identified as a key player in the DNA damage response to oxidative stress. Whether and to what extent these observations are causally linked remains unclear. Using immunofluorescence, fluorescence-activated nucleus sorting and single-nucleus sequencing, we report an oxidative stress-associated accumulation of nuclear hypophosphorylated tau in a subpopulation of cycling neurons confined in S phase in AD brains, near amyloid plaques. Tau downregulation in murine neurons revealed an essential role for tau to promote cell cycle progression to S phase and prevent apoptosis in response to oxidative stress. Our results suggest that tau holds oxidative stress-associated cycling neurons in S phase to escape cell death. Together, this study proposes a tau-dependent protective effect of neuronal cell cycle reactivation in AD brains and challenges the current view that the neuronal cell cycle is an early mediator of tau pathology., Competing Interests: Declaration of Competing Interests The authors declare that they have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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14. Tau Transfer via Extracellular Vesicles Disturbs the Astrocytic Mitochondrial System.
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Perbet R, Zufferey V, Leroux E, Parietti E, Espourteille J, Culebras L, Perriot S, Du Pasquier R, Bégard S, Deramecourt V, Déglon N, Toni N, Buée L, Colin M, and Richetin K
- Subjects
- Humans, Astrocytes metabolism, Brain metabolism, Protein Isoforms metabolism, tau Proteins metabolism, Tauopathies pathology
- Abstract
Tauopathies are neurodegenerative disorders involving the accumulation of tau isoforms in cell subpopulations such as astrocytes. The origins of the 3R and 4R isoforms of tau that accumulate in astrocytes remain unclear. Extracellular vesicles (EVs) were isolated from primary neurons overexpressing 1N3R or 1N4R tau or from human brain extracts (progressive supranuclear palsy or Pick disease patients or controls) and characterized (electron microscopy, nanoparticle tracking analysis (NTA), proteomics). After the isolated EVs were added to primary astrocytes or human iPSC-derived astrocytes, tau transfer and mitochondrial system function were evaluated (ELISA, immunofluorescence, MitoTracker staining). We demonstrated that neurons in which 3R or 4R tau accumulated had the capacity to transfer tau to astrocytes and that EVs were essential for the propagation of both isoforms of tau. Treatment with tau-containing EVs disrupted the astrocytic mitochondrial system, altering mitochondrial morphology, dynamics, and redox state. Although similar levels of 3R and 4R tau were transferred, 3R tau-containing EVs were significantly more damaging to astrocytes than 4R tau-containing EVs. Moreover, EVs isolated from the brain fluid of patients with different tauopathies affected mitochondrial function in astrocytes derived from human iPSCs. Our data indicate that tau pathology spreads to surrounding astrocytes via EVs-mediated transfer and modifies their function.
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- 2023
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15. Inhibition of Tau seeding by targeting Tau nucleation core within neurons with a single domain antibody fragment.
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Danis C, Dupré E, Zejneli O, Caillierez R, Arrial A, Bégard S, Mortelecque J, Eddarkaoui S, Loyens A, Cantrelle FX, Hanoulle X, Rain JC, Colin M, Buée L, and Landrieu I
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- Animals, Disease Models, Animal, Mice, Neurons metabolism, Repressor Proteins, tau Proteins genetics, Alzheimer Disease metabolism, Single-Domain Antibodies, Tauopathies metabolism
- Abstract
Tau proteins aggregate into filaments in brain cells in Alzheimer's disease and related disorders referred to as tauopathies. Here, we used fragments of camelid heavy-chain-only antibodies (VHHs or single domain antibody fragments) targeting Tau as immuno-modulators of its pathologic seeding. A VHH issued from the screen against Tau of a synthetic phage-display library of humanized VHHs was selected for its capacity to bind Tau microtubule-binding domain, composing the core of Tau fibrils. This parent VHH was optimized to improve its biochemical properties and to act in the intra-cellular compartment, resulting in VHH Z70. VHH Z70 precisely binds the PHF6 sequence, known for its nucleation capacity, as shown by the crystal structure of the complex. VHH Z70 was more efficient than the parent VHH to inhibit in vitro Tau aggregation in heparin-induced assays. Expression of VHH Z70 in a cellular model of Tau seeding also decreased the aggregation-reporting fluorescence signal. Finally, intra-cellular expression of VHH Z70 in the brain of an established tauopathy mouse seeding model demonstrated its capacity to mitigate accumulation of pathological Tau. VHH Z70, by targeting Tau inside brain neurons, where most of the pathological Tau resides, provides an immunological tool to target the intra-cellular compartment in tauopathies., Competing Interests: Declaration of interests A.A. and J.-C.R. are employees of Hybrigenic services., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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16. Extracellular vesicles: Major actors of heterogeneity in tau spreading among human tauopathies.
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Leroux E, Perbet R, Caillierez R, Richetin K, Lieger S, Espourteille J, Bouillet T, Bégard S, Danis C, Loyens A, Toni N, Déglon N, Deramecourt V, Schraen-Maschke S, Buée L, and Colin M
- Subjects
- Brain metabolism, Humans, tau Proteins genetics, tau Proteins metabolism, Alzheimer Disease genetics, Alzheimer Disease pathology, Extracellular Vesicles metabolism, Tauopathies genetics, Tauopathies pathology
- Abstract
Tauopathies are neurodegenerative diseases characterized by tau inclusions in brain cells. Seed-competent tau species have been suggested to spread from cell to cell in a stereotypical manner, indicating that this may involve a prion-like mechanism. Although the intercellular mechanisms of transfer are unclear, extracellular vesicles (EVs) could be potential shuttles. We assessed this in humans by preparing vesicles from fluids (brain-derived enriched EVs [BD-EVs]). These latter were isolated from different brain regions in various tauopathies, and their seeding potential was assessed in vitro and in vivo. We observed considerable heterogeneity among tauopathies and brain regions. The most striking evidence was coming mainly from Alzheimer's disease where the BD-EVs clearly contain pathological species that can induce tau lesions in vivo. The results support the hypothesis that BD-EVs participate in the prion-like propagation of tau pathology among tauopathies, and there may be implications for diagnostic and therapeutic strategies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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17. Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer's disease.
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Richetin K, Steullet P, Pachoud M, Perbet R, Parietti E, Maheswaran M, Eddarkaoui S, Bégard S, Pythoud C, Rey M, Caillierez R, Q Do K, Halliez S, Bezzi P, Buée L, Leuba G, Colin M, Toni N, and Déglon N
- Subjects
- Alzheimer Disease complications, Animals, Animals, Genetically Modified, Female, Humans, Memory Disorders etiology, Mice, Mice, Inbred C57BL, Nerve Net metabolism, Neurogenesis, Parvalbumins metabolism, Pregnancy, Psychomotor Performance, Rats, Spatial Memory, Synapses physiology, Alzheimer Disease metabolism, Alzheimer Disease psychology, Astrocytes metabolism, Dentate Gyrus metabolism, Memory Disorders metabolism, Memory Disorders psychology, tau Proteins metabolism
- Abstract
Alzheimer's disease (AD) is characterized by the accumulation of the tau protein in neurons, neurodegeneration and memory loss. However, the role of non-neuronal cells in this chain of events remains unclear. In the present study, we found accumulation of tau in hilar astrocytes of the dentate gyrus of individuals with AD. In mice, the overexpression of 3R tau specifically in hilar astrocytes of the dentate gyrus altered mitochondrial dynamics and function. In turn, these changes led to a reduction of adult neurogenesis, parvalbumin-expressing neurons, inhibitory synapses and hilar gamma oscillations, which were accompanied by impaired spatial memory performances. Together, these results indicate that the loss of tau homeostasis in hilar astrocytes of the dentate gyrus is sufficient to induce AD-like symptoms, through the impairment of the neuronal network. These results are important for our understanding of disease mechanisms and underline the crucial role of astrocytes in hippocampal function.
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- 2020
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18. Neuronal AMP-activated protein kinase hyper-activation induces synaptic loss by an autophagy-mediated process.
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Domise M, Sauvé F, Didier S, Caillerez R, Bégard S, Carrier S, Colin M, Marinangeli C, Buée L, and Vingtdeux V
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- Alzheimer Disease pathology, Animals, Enzyme Activation, Male, Mice, Inbred C57BL, AMP-Activated Protein Kinases metabolism, Autophagy, Nerve Net pathology, Synapses pathology
- Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss that leads to the development of cognitive deficits. Synapses are neuronal structures that play a crucial role in memory formation and are known to consume most of the energy used in the brain. Interestingly, AMP-activated protein kinase (AMPK), the main intracellular energy sensor, is hyper-activated in degenerating neurons in several neurodegenerative diseases, including AD. In this context, we asked whether AMPK hyper-activation could influence synapses' integrity and function. AMPK hyper-activation in differentiated primary neurons led to a time-dependent decrease in pre- and post-synaptic markers, which was accompanied by a reduction in synapses number and a loss of neuronal networks functionality. The loss of post-synaptic proteins was mediated by an AMPK-regulated autophagy-dependent pathway. Finally, this process was also observed in vivo, where AMPK hyper-activation primed synaptic loss. Overall, our data demonstrate that during energetic stress condition, AMPK might play a fundamental role in the maintenance of synaptic integrity, at least in part through the regulation of autophagy. Thus, AMPK might represent a potential link between energetic failure and synaptic integrity in neurodegenerative conditions such as AD.
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- 2019
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19. AMP-Activated Protein Kinase Is Essential for the Maintenance of Energy Levels during Synaptic Activation.
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Marinangeli C, Didier S, Ahmed T, Caillerez R, Domise M, Laloux C, Bégard S, Carrier S, Colin M, Marchetti P, Ghesquière B, Balschun D, Buée L, Kluza J, and Vingtdeux V
- Abstract
Although the brain accounts for only 2% of the total body mass, it consumes the most energy. Neuronal metabolism is tightly controlled, but it remains poorly understood how neurons meet their energy demands to sustain synaptic transmission. Here we provide evidence that AMP-activated protein kinase (AMPK) is pivotal to sustain neuronal energy levels upon synaptic activation by adapting the rate of glycolysis and mitochondrial respiration. Furthermore, this metabolic plasticity is required for the expression of immediate-early genes, synaptic plasticity, and memory formation. Important in this context, in neurodegenerative disorders such as Alzheimer disease, dysregulation of AMPK impairs the metabolic response to synaptic activation and processes that are central to neuronal plasticity. Altogether, our data provide proof of concept that AMPK is an essential player in the regulation of neuroenergetic metabolic plasticity induced in response to synaptic activation and that its deregulation might lead to cognitive impairments., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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20. Different tau species lead to heterogeneous tau pathology propagation and misfolding.
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Dujardin S, Bégard S, Caillierez R, Lachaud C, Carrier S, Lieger S, Gonzalez JA, Deramecourt V, Déglon N, Maurage CA, Frosch MP, Hyman BT, Colin M, and Buée L
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Brain metabolism, Brain pathology, Disease Models, Animal, Disease Progression, Female, Humans, Injections, Intraventricular, Male, Middle Aged, Mutation genetics, Phosphorylation, Protein Isoforms genetics, Protein Isoforms metabolism, Rats, Rats, Wistar, Severity of Illness Index, Proteostasis Deficiencies complications, Tauopathies etiology, Tauopathies genetics, Tauopathies metabolism, Tauopathies pathology, tau Proteins genetics, tau Proteins metabolism
- Abstract
Tauopathies are a heterogeneous group of pathologies characterized by tau aggregation inside neurons. Most of them are sporadic but certain tauopathies rely on tau gene (MAPT) mutations. They particularly differ from one to another by their different neuropathological signatures e.g. lesion shapes, regions affected and molecular composition of aggregates. Six isoforms of tau exist, but they do not all co-aggregate in each tauopathy but rather have a unique signature for each one. In some tauopathies such as Alzheimer's disease (AD), tau protein aggregation follows stereotypical anatomical stages. Recent data suggest that this progression is due to an active process of tau protein propagation from neuron-to-neuron. We wondered how tau isoforms or mutations could influence the process of tau aggregation and tau propagation. In human neuropathological material, we found that MAPT mutations induce a faster misfolding compared to tau found in sporadic AD patients. In the rat brain, we observed cell-to-cell transfer of non-pathological tau species irrespective of the tested isoform or presence of a mutation. By contrast, we found that the species of tau impact the propagation of tau pathology markers such as hyperphosphorylation and misfolding. Indeed, misfolding and hyperphosphorylated tau proteins do not spread at the same rate when tau is mutated, or the isoform composition is modified. These results clearly argue for the existence of specific folding properties of tau depending on isoforms or mutations impacting the behavior of pathological tau species.
- Published
- 2018
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21. Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies.
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Tardivel M, Bégard S, Bousset L, Dujardin S, Coens A, Melki R, Buée L, and Colin M
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- Actins genetics, Actins metabolism, Animals, Biological Transport physiology, Cell Line, Cerebral Cortex metabolism, Cerebral Cortex ultrastructure, Extracellular Space metabolism, Genetic Vectors, Humans, Lentivirus genetics, Luminescent Proteins genetics, Luminescent Proteins metabolism, Mice, Myosins metabolism, Rats, Wistar, Tubulin genetics, Tubulin metabolism, tau Proteins genetics, Cell Communication, Neurons metabolism, Neurons ultrastructure, tau Proteins metabolism
- Abstract
A given cell makes exchanges with its neighbors through a variety of means ranging from diffusible factors to vesicles. Cells use also tunneling nanotubes (TNTs), filamentous-actin-containing membranous structures that bridge and connect cells. First described in immune cells, TNTs facilitate HIV-1 transfer and are found in various cell types, including neurons. We show that the microtubule-associated protein Tau, a key player in Alzheimer's disease, is a bona fide constituent of TNTs. This is important because Tau appears beside filamentous actin and myosin 10 as a specific marker of these fine protrusions of membranes and cytosol that are difficult to visualize. Furthermore, we observed that exogenous Tau species increase the number of TNTs established between primary neurons, thereby facilitating the intercellular transfer of Tau fibrils. In conclusion, Tau may contribute to the formation and function of the highly dynamic TNTs that may be involved in the prion-like propagation of Tau assemblies.
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- 2016
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22. Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin.
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Mansuroglu Z, Benhelli-Mokrani H, Marcato V, Sultan A, Violet M, Chauderlier A, Delattre L, Loyens A, Talahari S, Bégard S, Nesslany F, Colin M, Souès S, Lefebvre B, Buée L, Galas MC, and Bonnefoy E
- Subjects
- Animals, Brain metabolism, Chromobox Protein Homolog 5, Chromosomal Proteins, Non-Histone genetics, DNA Breaks, Epigenesis, Genetic genetics, Histones genetics, Humans, Lysine genetics, Mice, Mice, Knockout, Centromere genetics, DNA Repair genetics, Heterochromatin genetics, Neurons metabolism, Transcription, Genetic genetics, tau Proteins genetics
- Abstract
Pericentromeric heterochromatin (PCH) gives rise to highly dense chromatin sub-structures rich in the epigenetic mark corresponding to the trimethylated form of lysine 9 of histone H3 (H3K9me3) and in heterochromatin protein 1α (HP1α), which regulate genome expression and stability. We demonstrate that Tau, a protein involved in a number of neurodegenerative diseases including Alzheimer's disease (AD), binds to and localizes within or next to neuronal PCH in primary neuronal cultures from wild-type mice. Concomitantly, we show that the clustered distribution of H3K9me3 and HP1α, two hallmarks of PCH, is disrupted in neurons from Tau-deficient mice (KOTau). Such altered distribution of H3K9me3 that could be rescued by overexpressing nuclear Tau protein was also observed in neurons from AD brains. Moreover, the expression of PCH non-coding RNAs, involved in PCH organization, was disrupted in KOTau neurons that displayed an abnormal accumulation of stress-induced PCH DNA breaks. Altogether, our results demonstrate a new physiological function of Tau in directly regulating neuronal PCH integrity that appears disrupted in AD neurons.
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- 2016
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23. Ectosomes: a new mechanism for non-exosomal secretion of tau protein.
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Dujardin S, Bégard S, Caillierez R, Lachaud C, Delattre L, Carrier S, Loyens A, Galas MC, Bousset L, Melki R, Aurégan G, Hantraye P, Brouillet E, Buée L, and Colin M
- Subjects
- Animals, Cells, Cultured, Embryo, Mammalian cytology, Exosomes metabolism, Extracellular Fluid metabolism, Humans, Microscopy, Electron, Neurons cytology, Neurons metabolism, Rats, Rats, Wistar, Cell-Derived Microparticles metabolism, tau Proteins metabolism
- Abstract
Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested that Tau may be secreted and play a role in neural network signalling. However, once deregulated, secreted Tau may also participate in the spreading of Tau pathology in hierarchical pathways of neurodegeneration. The mechanisms underlying neuron-to-neuron Tau transfer are still unknown; given the known role of extra-cellular vesicles in cell-to-cell communication, we wondered whether these vesicles could carry secreted Tau. We found, among vesicles, that Tau is predominately secreted in ectosomes, which are plasma membrane-originating vesicles, and when it accumulates, the exosomal pathway is activated.
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- 2014
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24. Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies.
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Dujardin S, Lécolle K, Caillierez R, Bégard S, Zommer N, Lachaud C, Carrier S, Dufour N, Aurégan G, Winderickx J, Hantraye P, Déglon N, Colin M, and Buée L
- Subjects
- Animals, Brain pathology, Cell Differentiation genetics, Cells, Cultured, Disease Models, Animal, Disease Progression, Embryo, Mammalian, Gene Transfer Techniques, Humans, Microfluidic Analytical Techniques, Microscopy, Confocal, Microtubule-Associated Proteins genetics, Microtubule-Associated Proteins metabolism, Mutation genetics, Protein Transport physiology, RNA, Messenger metabolism, Rats, Rats, Wistar, Neurons metabolism, Tauopathies pathology, tau Proteins metabolism
- Abstract
Background: In sporadic Tauopathies, neurofibrillary degeneration (NFD) is characterised by the intraneuronal aggregation of wild-type Tau proteins. In the human brain, the hierarchical pathways of this neurodegeneration have been well established in Alzheimer's disease (AD) and other sporadic tauopathies such as argyrophilic grain disorder and progressive supranuclear palsy but the molecular and cellular mechanisms supporting this progression are yet not known. These pathways appear to be associated with the intercellular transmission of pathology, as recently suggested in Tau transgenic mice. However, these conclusions remain ill-defined due to a lack of toxicity data and difficulties associated with the use of mutant Tau., Results: Using a lentiviral-mediated rat model of hippocampal NFD, we demonstrated that wild-type human Tau protein is axonally transferred from ventral hippocampus neurons to connected secondary neurons even at distant brain areas such as olfactory and limbic systems indicating a trans-synaptic protein transfer. Using different immunological tools to follow phospho-Tau species, it was clear that Tau pathology generated using mutated Tau remains near the IS whereas it spreads much further using the wild-type one., Conclusion: Taken together, these results support a novel mechanism for Tau protein transfer compared to previous reports based on transgenic models with mutant cDNA. It also demonstrates that mutant Tau proteins are not suitable for the development of experimental models helpful to validate therapeutic intervention interfering with Tau spreading.
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- 2014
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25. Lentiviral delivery of the human wild-type tau protein mediates a slow and progressive neurodegenerative tau pathology in the rat brain.
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Caillierez R, Bégard S, Lécolle K, Deramecourt V, Zommer N, Dujardin S, Loyens A, Dufour N, Aurégan G, Winderickx J, Hantraye P, Déglon N, Buée L, and Colin M
- Subjects
- Animals, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Rats, Rats, Wistar, Tauopathies genetics, tau Proteins genetics, Brain metabolism, Brain pathology, Lentivirus genetics, Tauopathies metabolism, tau Proteins metabolism
- Abstract
Most models for tauopathy use a mutated form of the Tau gene, MAPT, that is found in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) and that leads to rapid neurofibrillary degeneration (NFD). Use of a wild-type (WT) form of human Tau protein to model the aggregation and associated neurodegenerative processes of Tau in the mouse brain has thus far been unsuccessful. In the present study, we generated an original "sporadic tauopathy-like" model in the rat hippocampus, encoding six Tau isoforms as found in humans, using lentiviral vectors (LVs) for the delivery of a human WT Tau. The overexpression of human WT Tau in pyramidal neurons resulted in NFD, the morphological characteristics and kinetics of which reflected the slow and sporadic neurodegenerative processes observed in sporadic tauopathies, unlike the rapid neurodegenerative processes leading to cell death and ghost tangles triggered by the FTDP-17 mutant Tau P301L. This new model highlights differences in the molecular and cellular mechanisms underlying the pathological processes induced by WT and mutant Tau and suggests that preference should be given to animal models using WT Tau in the quest to understand sporadic tauopathies.
- Published
- 2013
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26. Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.
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Ando K, Dourlen P, Sambo AV, Bretteville A, Bélarbi K, Vingtdeux V, Eddarkaoui S, Drobecq H, Ghestem A, Bégard S, Demey-Thomas E, Melnyk P, Smet C, Lippens G, Maurage CA, Caillet-Boudin ML, Verdier Y, Vinh J, Landrieu I, Galas MC, Blum D, Hamdane M, Sergeant N, and Buée L
- Subjects
- Acetylation, Adult, Aged, Aged, 80 and over, Alzheimer Disease metabolism, Animals, Biomarkers metabolism, Cell Line, Tumor, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Transgenic, Middle Aged, NIMA-Interacting Peptidylprolyl Isomerase, Oxidation-Reduction, Phosphorylation physiology, Proline metabolism, Proteome, Serine metabolism, Brain metabolism, Peptidylprolyl Isomerase metabolism, Protein Processing, Post-Translational physiology, Tauopathies metabolism, tau Proteins metabolism
- Abstract
A prerequisite to dephosphorylation at Ser-Pro or Thr-Pro motifs is the isomerization of the imidic peptide bond preceding the proline. The peptidyl-prolyl cis/trans isomerase named Pin1 catalyzes this mechanism. Through isomerization, Pin1 regulates the function of a growing number of targets including the microtubule-associated tau protein and is supposed to be deregulated Alzheimer's disease (AD). Using proteomics, we showed that Pin1 is posttranslationally modified on more than 5 residues, comprising phosphorylation, N-acetylation, and oxidation. Although Pin1 expression remained constant, Pin1 posttranslational two-dimensional pattern was modified by tau overexpression in a tau-inducible neuroblastoma cell line, in our THY-Tau22 mouse model of tauopathy as well as in AD. Interestingly, in all of these systems, Pin1 modifications were very similar. In AD brain tissue when compared with control, Pin1 is hyperphosphorylated at serine 16 and found in the most insoluble hyperphosphorylated tau fraction of AD brain tissue. Furthermore, in all tau pathology conditions, acetylation of Pin1 may also contribute to the differences observed. In conclusion, Pin1 displays several posttranslational modifications, which are specific in tauopathies and may be useful as biomarker., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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27. Nuclear tau, a key player in neuronal DNA protection.
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Sultan A, Nesslany F, Violet M, Bégard S, Loyens A, Talahari S, Mansuroglu Z, Marzin D, Sergeant N, Humez S, Colin M, Bonnefoy E, Buée L, and Galas MC
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Animals, Cell Nucleus genetics, Cell Nucleus pathology, Cells, Cultured, DNA genetics, Humans, Mice, Mice, Knockout, Neurons pathology, Phosphorylation genetics, tau Proteins genetics, Cell Nucleus metabolism, DNA metabolism, Heat-Shock Response, Neurons metabolism, tau Proteins metabolism
- Abstract
Tau, a neuronal protein involved in neurodegenerative disorders such as Alzheimer disease, which is primarily described as a microtubule-associated protein, has also been observed in the nuclei of neuronal and non-neuronal cells. However, the function of the nuclear form of Tau in neurons has not yet been elucidated. In this work, we demonstrate that acute oxidative stress and mild heat stress (HS) induce the accumulation of dephosphorylated Tau in neuronal nuclei. Using chromatin immunoprecipitation assays, we demonstrate that the capacity of endogenous Tau to interact with neuronal DNA increased following HS. Comet assays performed on both wild-type and Tau-deficient neuronal cultures showed that Tau fully protected neuronal genomic DNA against HS-induced damage. Interestingly, HS-induced DNA damage observed in Tau-deficient cells was completely rescued after the overexpression of human Tau targeted to the nucleus. These results highlight a novel role for nuclear Tau as a key player in early stress response.
- Published
- 2011
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28. Two-dimensional electrophoresis of tau mutants reveals specific phosphorylation pattern likely linked to early tau conformational changes.
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Bretteville A, Ando K, Ghestem A, Loyens A, Bégard S, Beauvillain JC, Sergeant N, Hamdane M, and Buée L
- Subjects
- Animals, Cell Line, Tumor, Humans, Mice, Mice, Transgenic, Microscopy, Electron, Phosphorylation, Protein Conformation, tau Proteins chemistry, tau Proteins genetics, Electrophoresis, Gel, Two-Dimensional methods, Mutation, tau Proteins metabolism
- Abstract
The role of Tau phosphorylation in neurofibrillary degeneration linked to Alzheimer's disease remains to be established. While transgenic mice based on FTDP-17 Tau mutations recapitulate hallmarks of neurofibrillary degeneration, cell models could be helpful for exploratory studies on molecular mechanisms underlying Tau pathology. Here, "human neuronal cell lines" overexpressing Wild Type or mutated Tau were established. Two-dimensional electrophoresis highlights that mutated Tau displayed a specific phosphorylation pattern, which occurs in parallel to the formation of Tau clusters as visualized by electron microscopy. In fact, this pattern is also displayed before Tau pathology onset in a well established mouse model relevant to Tau aggregation in Alzheimer's disease. This study suggests first that pathological Tau mutations may change the distribution of phosphate groups. Secondly, it is possible that this molecular event could be one of the first Tau modifications in the neurofibrillary degenerative process, as this phenomenon appears prior to Tau pathology in an in vivo model and is linked to early steps of Tau nucleation in Tau mutants cell lines. Such cell lines consist in suitable and evolving models to investigate additional factors involved in molecular pathways leading to whole Tau aggregation.
- Published
- 2009
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29. Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies.
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Vingtdeux V, Hamdane M, Loyens A, Gelé P, Drobeck H, Bégard S, Galas MC, Delacourte A, Beauvillain JC, Buée L, and Sergeant N
- Subjects
- Animals, Brain embryology, Cell Line, Tumor, Endosomes metabolism, Humans, Macrolides pharmacology, Models, Biological, Neuroblastoma metabolism, Neurons metabolism, Organelles metabolism, Protein Structure, Tertiary, Rats, Rats, Wistar, Amyloid metabolism, Enzyme Inhibitors pharmacology
- Abstract
Amyloid precursor protein (APP) metabolism is central to the pathogenesis of Alzheimer disease. We showed recently that the amyloid intracellular domain (AICD), which is released by gamma-secretase cleavage of APP C-terminal fragments (CTFs), is strongly increased in cells treated with alkalizing drugs (Vingtdeux, V., Hamdane, M., Bégard, S., Loyens, A., Delacourte, A., Beauvillain, J.-C., Buée, L., Marambaud, P., and Sergeant, N. (2007) Neurobiol. Dis. 25, 686-696). Herein, we aimed to determine the cell compartment in which AICD accumulates. We show that APP-CTFs and AICD are present in multivesicular structures. Multivesicular bodies contain intraluminal vesicles (known as exosomes) when released in the extracellular space. We demonstrate that APP, APP-CTFs, and AICD are integrated and secreted within exosomes in differentiated neuroblastoma and primary neuronal culture cells. Together with recent data showing that amyloid-beta is also found in exosomes, our data show that multivesicular bodies are essential organelles for APP metabolism and that all APP metabolites can be secreted in the extracellular space.
- Published
- 2007
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30. Intracellular pH regulates amyloid precursor protein intracellular domain accumulation.
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Vingtdeux V, Hamdane M, Bégard S, Loyens A, Delacourte A, Beauvillain JC, Buée L, Marambaud P, and Sergeant N
- Subjects
- Alkalies metabolism, Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Protein Precursor genetics, Animals, COS Cells, Cadherins metabolism, Cell Line, Tumor, Chlorocebus aethiops, Enzyme Inhibitors pharmacology, Humans, Kidney cytology, Lysosomes metabolism, Macrolides pharmacology, Neuroblastoma, Protein Structure, Tertiary, Receptors, Notch metabolism, Solubility, Transfection, Amyloid beta-Protein Precursor chemistry, Amyloid beta-Protein Precursor metabolism, Hydrogen-Ion Concentration drug effects
- Abstract
The amyloid precursor protein (APP) metabolism is central to pathogenesis of Alzheimer's disease (AD). Parenchymal amyloid deposits, a neuropathological hallmark of AD, are composed of amyloid-beta peptides (Abeta). Abeta derives from the amyloid precursor protein (APP) by sequential cleavages by beta- and gamma-secretases. Gamma-secretase cleavage releases the APP intracellular domain (AICD), suggested to mediate a nuclear signaling. Physiologically, AICD is seldom detected and thus supposed to be rapidly degraded. The mechanisms responsible of its degradation remain unknown. We used a pharmacological approach and showed that several alkalizing drugs induce the accumulation of AICD in neuroblastoma SY5Y cell lines stably expressing APP constructs. Moreover, alkalizing drugs induce AICD accumulation in naive SY5Y, HEK and COS cells. This accumulation is not mediated by the proteasome or metallopeptidases and is not the result of an increased gamma-secretase activity since the gamma-secretase cleavage of Notch1 and N-Cadherin is not affected by alkalizing drug treatments. Altogether, our data demonstrate for the first time that alkalizing drugs induce the accumulation of AICD, a mechanism likely mediated by the endosome/lysosome pathway.
- Published
- 2007
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31. Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits.
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Schindowski K, Bretteville A, Leroy K, Bégard S, Brion JP, Hamdane M, and Buée L
- Subjects
- Aging, Animals, Behavior, Animal, Disease Models, Animal, Gliosis pathology, Hippocampus cytology, Hippocampus pathology, Hippocampus ultrastructure, Humans, Mice, Mice, Transgenic, Nerve Degeneration, Neurofibrillary Tangles ultrastructure, Phosphorylation, Protein Conformation, Synaptic Transmission physiology, tau Proteins chemistry, tau Proteins metabolism, Alzheimer Disease pathology, Memory Disorders pathology, Motor Skills Disorders pathology, Mutation genetics, Synapses pathology, tau Proteins genetics
- Abstract
Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer's disease and other tauopathies. However, motor dysfunction and dystonic posture interfering with behavioral testing are the most common undesirable effects of tau transgenic mice. Therefore, we have generated a novel mouse model (THY-Tau22) that expresses human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2-promotor, displaying tau pathology in the absence of any motor dysfunction. THY-Tau22 shows hyperphosphorylation of tau on several Alzheimer's disease-relevant tau epitopes (AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422), neurofibrillary tangle-like inclusions (Gallyas and MC1-positive) with rare ghost tangles and PHF-like filaments, as well as mild astrogliosis. These mice also display deficits in hippocampal synaptic transmission and impaired behavior characterized by increased anxiety, delayed learning from 3 months, and reduced spatial memory at 10 months. There are no signs of motor deficits or changes in motor activity at any age investigated. This mouse model therefore displays the main features of tau pathology and several of the pathophysiological disturbances observed during neurofibrillary degeneration. This model will serve as an experimental tool in future studies to investigate mechanisms underlying cognitive deficits during pathogenic tau aggregation.
- Published
- 2006
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32. The peptidylprolyl cis/trans-isomerase Pin1 modulates stress-induced dephosphorylation of Tau in neurons. Implication in a pathological mechanism related to Alzheimer disease.
- Author
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Galas MC, Dourlen P, Bégard S, Ando K, Blum D, Hamdane M, and Buée L
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Animals, Catalysis, Enzyme Activation, Enzyme Inhibitors pharmacology, Hydrogen Peroxide pharmacology, Microtubules metabolism, Naphthoquinones pharmacology, Peptides chemistry, Phosphorylation, Rats, tau Proteins metabolism, Adaptor Proteins, Signal Transducing physiology, Alzheimer Disease metabolism, Neurons metabolism, tau Proteins chemistry
- Abstract
Deregulation of Tau phosphorylation is a key question in Alzheimer disease pathogenesis. Recently, Pin1, a peptidylprolyl cis/trans-isomerase, was proposed to be a new modulator in Tau phosphorylation in Alzheimer disease. In vitro, Pin1 was reported to present a high affinity for both Thr(P)-231, a crucial site for microtubule binding, and Thr(P)-212. In fact, Pin1 may facilitate Thr(P)-231 dephosphorylation by protein phosphatase 2A through trans isomerization of the Thr(P)-Pro peptide bound. However, whether Pin1 binding to Tau leads to isomerization of a single site or of multiple Ser/Thr(P)-Pro sites in vivo is still unknown. In the present study, Pin1 involvement was investigated in stress-induced Tau dephosphorylation with protein phosphatase 2A activation. Both oxidative (H2O2) and heat stresses induced hypophosphorylation of a large set of phospho-Tau epitopes in primary cortical cultures. In both cases, juglone, a Pin1 pharmacological inhibitor, partially prevented dephosphorylation of Tau at Thr-231 among a set of phosphoepitopes tested. Moreover, Pin1 is physiologically found in neurons and partially co-localized with Tau. Furthermore, in Pin1-deficient neuronal primary cultures, H2O2 stress-induced Tau dephosphorylation at Thr(P)-231 was significantly lower than in wild type neurons. Finally, Pin1 transfection in Pin1-deficient neuronal cell cultures allowed for rescuing the effect of H2O2 stress-induced Tau dephosphorylation, whereas a Pin1 catalytic mutant did not. This is the first demonstration of an in situ Pin1 involvement in a differential Tau dephosphorylation on the full-length multiphosphorylated substrate.
- Published
- 2006
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33. Pin1 allows for differential Tau dephosphorylation in neuronal cells.
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Hamdane M, Dourlen P, Bretteville A, Sambo AV, Ferreira S, Ando K, Kerdraon O, Bégard S, Geay L, Lippens G, Sergeant N, Delacourte A, Maurage CA, Galas MC, and Buée L
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease physiopathology, Amino Acid Sequence physiology, Animals, Binding Sites physiology, Brain pathology, Brain physiopathology, Cell Differentiation physiology, Cell Line, Tumor, Cells, Cultured, Humans, NIMA-Interacting Peptidylprolyl Isomerase, Neurofibrillary Tangles genetics, Neurofibrillary Tangles pathology, Neurons pathology, Peptidylprolyl Isomerase genetics, Phosphorylation, Protein Binding physiology, Rats, Threonine metabolism, Up-Regulation physiology, tau Proteins chemistry, Brain metabolism, Neurofibrillary Tangles metabolism, Neurons metabolism, Peptidylprolyl Isomerase metabolism, tau Proteins metabolism
- Abstract
Neurofibrillary degeneration is likely to be related to abnormal Tau phosphorylation and aggregation. Among abnormal Tau phosphorylation sites, pThr231 is of particular interest since it is associated with early stages of Alzheimer's disease and is a binding site of Pin1, a peptidyl-prolyl cis/trans isomerase mainly involved in cell cycle regulation. In the present work, Pin1 level was found strongly increased during neuronal differentiation and tightly correlated with Tau dephosphorylation at Thr231. Likewise, we showed in cellular model that Pin1 allowed for specific Tau dephosphorylation at Thr231, whereas other phosphorylation sites were unchanged. Moreover, cells displaying Tau phosphorylation at Thr231 did not show any Pin1 nuclear depletion. Altogether, these data indicate that Pin1 has key function(s) in neuron and is at least involved in the regulation of Tau phosphorylation at relevant sites. Hence, Pin1 dysfunction, unlikely by nuclear depletion, may have critical consequences on Tau pathological aggregation and neuronal death.
- Published
- 2006
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34. Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism.
- Author
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Vingtdeux V, Hamdane M, Gompel M, Bégard S, Drobecq H, Ghestem A, Grosjean ME, Kostanjevecki V, Grognet P, Vanmechelen E, Buée L, Delacourte A, and Sergeant N
- Subjects
- Alzheimer Disease physiopathology, Amino Acid Sequence physiology, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides biosynthesis, Amyloid beta-Protein Precursor chemistry, Animals, Aspartic Acid Endopeptidases, Brain physiopathology, Enzyme Inhibitors pharmacology, Humans, JNK Mitogen-Activated Protein Kinases metabolism, Membrane Proteins metabolism, Peptide Fragments chemistry, Phosphorylation, Presenilin-1, Protein Processing, Post-Translational physiology, Protein Structure, Tertiary physiology, Rabbits, Threonine metabolism, Tumor Cells, Cultured, Alzheimer Disease metabolism, Amyloid beta-Protein Precursor metabolism, Brain metabolism, Endopeptidases metabolism, Peptide Fragments metabolism
- Abstract
In Alzheimer's disease, the complex catabolism of amyloid precursor protein (APP) leads to the production of amyloid-beta (Abeta) peptide, the major component of amyloid deposits. APP is cleaved by beta- and alpha-secretases to generate APP carboxy-terminal fragments (CTFs). Abeta peptide and amyloid intracellular domain are resulting from the cleavage of APP-CTFs by the gamma-secretase. In the present study, we hypothesize that post-translational modification of APP-CTFs could modulate their processing by the gamma-secretase. Inhibition of the gamma-secretase was shown to increase the total amount of APP-CTFs. Moreover, we showed that this increase was more marked among the phosphorylated variants and directly related to the activity of the gamma-secretase, as shown by kinetics analyses. Phosphorylated CTFs were shown to associate to presenilin 1, a major protein of the gamma-secretase complex. The phosphorylation of CTFs at the threonine 668 resulting of the c-Jun N-terminal kinase activation was shown to enhance their degradation by the gamma-secretase. Altogether, our results demonstrated that phosphorylated CTFs can be the substrates of the gamma-secretase and that an increase in the phosphorylation of APP-CTFs facilitates their processing by gamma-secretase.
- Published
- 2005
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35. p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death.
- Author
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Hamdane M, Bretteville A, Sambo AV, Schindowski K, Bégard S, Delacourte A, Bertrand P, and Buée L
- Subjects
- Apoptosis, Blotting, Western, Cell Cycle, Cell Cycle Proteins metabolism, Cell Death, Cell Line, Tumor, Cell Nucleus metabolism, Cyclin-Dependent Kinase 5, Cytoplasm metabolism, DNA-Binding Proteins metabolism, E2F Transcription Factors, Humans, Immunoblotting, Immunoprecipitation, Nerve Growth Factor metabolism, Neurons metabolism, Phosphorylation, Purines pharmacology, Roscovitine, Time Factors, Transcription Factors metabolism, Cyclin-Dependent Kinases metabolism, Nerve Tissue Proteins metabolism, Neurons pathology, Retinoblastoma Protein metabolism
- Abstract
In large models of neuronal cell death, there is a tight correlation between Cdk5 deregulation and cell-cycle dysfunction. However, pathways that link Cdk5 to the cell cycle during neuronal death are still unclear. We have investigated the molecular events that precede p25/Cdk5-triggered neuronal death using a neuronal cell line that allows inducible p25 expression. In this system, no sign of apoptosis was seen before 24 hours of p25 induction. Thus, at that time, cell-cycle-regulatory proteins were analysed by immunoblotting and some of them showed a significant deregulation. Interestingly, after time-course experiments, the earliest feature correlated with p25 expression was the phosphorylation of the retinoblastoma protein (Rb). Indeed, this phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a Cdk5 inhibitor, roscovitine, which does not inhibit the usual Rb cyclin-D kinases Cdk4 and Cdk6. Furthermore, analyses of levels and subcellular localization of Cdk-related cyclins did not reveal any change following Cdk5 activation, arguing for a direct effect of Cdk5 activity on Rb protein. This latter result was clearly demonstrated by in vitro kinase assays showing that the p25-Cdk5 complex in our cell system phosphorylates Rb directly without the need for any intermediary kinase activity. Hence, Rb might be an appropriate candidate that connects Cdk5 to cell-cycle deregulation during neuronal cell death.
- Published
- 2005
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36. Stable-tau overexpression in human neuroblastoma cells: an open door for explaining neuronal death in tauopathies.
- Author
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Delobel P, Mailliot C, Hamdane M, Sambo AV, Bégard S, Violleau A, Delacourte A, and Buée L
- Subjects
- Cell Line, Tumor, Humans, Neuroblastoma, RNA, Messenger genetics, Recombinant Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tauopathies genetics, Tauopathies pathology, Transfection, tau Proteins metabolism, Apoptosis physiology, Cell Death physiology, Neurodegenerative Diseases pathology, Neurons pathology, tau Proteins genetics
- Abstract
Many neurodegenerative disorders referred to as "tauopathies" are characterized by the accumulation and aggregation of Tau proteins into filaments. In these pathologies, Tau proteins are hyperphosphorylated and also abnormally phosphorylated. Moreover, they differ from each other by the preferential aggregation of isoforms exhibiting either three microtubule-binding repeats (3R) or four repeats (4R) Tau. To investigate the effects of an intracellular accumulation of Tau, we stably transfected neuroblastoma cell line SY5Y with either 3R or 4R Tau. Our data showed that an increase in intracellular Tau expression has led to their hyperphosphorylation. Conversely, an abnormal Tau phosphorylation and/or aggregation were never observed. Furthermore, SY5Y cells transfected with 4R Tau showed an increased susceptibility to cell death. Finally, in apoptotic conditions, Tau proteins were degraded at their carboxy terminus by caspase, leading to an apparent decrease in Tau phosphorylation in this region. Because truncated Tau generated during apoptosis are not commonly found in Tau aggregates, apoptotic processes may not be of interest in neurofibrillary degeneration.
- Published
- 2003
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37. Neurofibrillary degeneration of the Alzheimer-type: an alternate pathway to neuronal apoptosis?
- Author
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Hamdane M, Delobel P, Sambo AV, Smet C, Bégard S, Violleau A, Landrieu I, Delacourte A, Lippens G, Flament S, and Buée L
- Subjects
- Animals, Cell Cycle, Humans, Mitosis, NIMA-Interacting Peptidylprolyl Isomerase, Neurofibrillary Tangles pathology, Peptidylprolyl Isomerase physiology, Phosphorylation, tau Proteins metabolism, Alzheimer Disease pathology, Apoptosis, Nerve Degeneration pathology
- Abstract
Neuronal death is a process which may be either physiological or pathological. Apoptosis and necrosis are two of these processes which are particularly studied. However, in neurodegenerative disorders, some neurons escape to these types of death and "agonize" in a process referred to as neurofibrillary degeneration. Neurofibrillary degeneration is characterized by the intraneuronal aggregation of abnormally phosphorylated microtubule-associated Tau proteins. A number of studies have reported a reactivation of the cell cycle in the neurofibrillary degeneration process. This reactivation of the cell cycle is reminiscent of the initiation of apoptosis in post-mitotic cells where G1/S markers including cyclin D1 and cdk4/6, are commonly found. However, in neurons exhibiting neurofibrillary degeneration, both G1/S and G2/M markers are found suggesting that they do not follow the classical apoptosis and an aberrant cell cycle occurs. This aberrant response leading to neurofibrillary degeneration may be triggered by the sequential combination of three partners: the complex Cdk5/p25 induces both apoptosis and the "abnormal mitotic Tau phosphorylation". These mitotic epitopes may allow for the nuclear depletion of Pin1. This latter may be responsible for escaping classical apoptosis in a subset of neurons. Since neurofibrillary degeneration is likely to be a third way to die, molecular mechanisms leading to changes in Tau phosphorylation including activation of kinases such as cdk5 or other regulators such as Pin1 could be important drug targets as they are possibly involved in early stages of neurodegeneration.
- Published
- 2003
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38. Mitotic-like tau phosphorylation by p25-Cdk5 kinase complex.
- Author
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Hamdane M, Sambo AV, Delobel P, Bégard S, Violleau A, Delacourte A, Bertrand P, Benavides J, and Buée L
- Subjects
- Blotting, Western, Cell Differentiation, Chromobox Protein Homolog 5, Cyclin-Dependent Kinase 5, Cytosol metabolism, Detergents pharmacology, Enzyme Inhibitors pharmacology, Epitopes, Genetic Vectors, Humans, Mitochondria metabolism, Nerve Tissue Proteins metabolism, Neurons metabolism, Phosphorylation, Precipitin Tests, Protein Binding, Sodium Dodecyl Sulfate pharmacology, Subcellular Fractions, Tetracycline pharmacology, Time Factors, Transfection, Tumor Cells, Cultured, Cyclin-Dependent Kinases metabolism, Mitosis, Nerve Tissue Proteins chemistry, tau Proteins metabolism
- Abstract
Among tau phosphorylation sites, some phosphoepitopes referred to as abnormal ones are exclusively found on tau aggregated into filaments in Alzheimer's disease. Recent data suggested that molecular mechanisms similar to those encountered during mitosis may play a role in abnormal tau phosphorylation. In particular, TG-3 phosphoepitope is associated with early stages of neurofibrillary tangles (NFTs). In this study, we reported a suitable cell model consisting of SH-SY5Y cells stably transfected with an inducible p25 expression vector. It allows investigation of tau phosphorylation by p25-Cdk5 kinase complex in a neuronal context and avoiding p25-induced cytotoxicity. Immunoblotting analyses showed that p25-Cdk5 strongly phosphorylates tau protein not only at the AT8 epitope but also at the AT180 epitope and at the Alzheimer's mitotic epitope TG-3. Further biochemical analyses showed that abnormal phosphorylated tau accumulated in cytosol as a microtubule-free form, suggesting its impact on tau biological activity. Since tau abnormal phosphorylation occurred in dividing cells, TG-3 immunoreactivity was also investigated in differentiated neuronal ones, and both TG-3-immunoreactive tau and nucleolin, another early marker for NFT, were also generated. These data suggest that p25-Cdk5 is responsible for the mitotic-like phosphoepitopes present in NFT and argue for a critical role of Cdk5 in neurodegenerative mechanisms.
- Published
- 2003
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39. Pin1: a therapeutic target in Alzheimer neurodegeneration.
- Author
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Hamdane M, Smet C, Sambo AV, Leroy A, Wieruszeski JM, Delobel P, Maurage CA, Ghestem A, Wintjens R, Bégard S, Sergeant N, Delacourte A, Horvath D, Landrieu I, Lippens G, and Buée L
- Subjects
- Alzheimer Disease drug therapy, Cell Line, Cyclin D1 metabolism, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, NIMA-Interacting Peptidylprolyl Isomerase, Naphthoquinones pharmacology, Neuroblastoma metabolism, Neurons pathology, Peptidylprolyl Isomerase antagonists & inhibitors, Peptidylprolyl Isomerase genetics, Phosphopyruvate Hydratase metabolism, Phosphorylation, Protein Binding physiology, Protein Structure, Tertiary physiology, Spectrometry, Fluorescence, tau Proteins chemistry, tau Proteins metabolism, Alzheimer Disease metabolism, Neurons enzymology, Peptidylprolyl Isomerase chemistry, Peptidylprolyl Isomerase metabolism
- Abstract
In Alzheimer's disease, the peptidyl prolyl cis/trans isomerase Pin1 binds to phospho-Thr231 on Tau proteins and, hence, is found within degenerating neurons, where it is associated to the large amounts of abnormally phosphorylated Tau proteins. Conversely, Pin1 may restore the tubulin polymerization function of these hyperphosphorylated Tau. In the present work, we investigated, both at the cellular and molecular levels, the role of Pin1 in Alzheimer's disease through the study of its interactions with phosphorylated Tau proteins. We also showed that in neuronal cells, Pin1 upregulates the expression of cyclin D1. This, in turn, could facilitate the transition from quiescence to the G1 phase (re-entry in cell cycle) in a neuron and, subsequently, neuronal dedifferentiation and apoptosis. The involvement of Pin1 in the G0/G1 transition in neurons points to its function as a good target for the development of new therapeutic strategies in neurodegenerative disorders.
- Published
- 2002
- Full Text
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40. [Tau story: from frontotemporal dementia to other tauopathies].
- Author
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Buée L, Hamdane M, Delobel P, Sambo AV, Bégard S, Ghestem A, Sergeant N, and Delacourte A
- Subjects
- Alternative Splicing, Alzheimer Disease genetics, Chromosomes, Human, Pair 17, Gene Expression, Humans, Mutation, Neurodegenerative Diseases genetics, Neurofibrillary Tangles chemistry, Phosphorylation, Protein Isoforms analysis, tau Proteins analysis, tau Proteins chemistry, Dementia genetics, tau Proteins genetics
- Abstract
Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of fibrillar lesions described in Alzheimer's disease and numerous neurodegenerative disorders referred to as 'tauopathies'. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, the recent discovery of tau gene mutations in fronto-temporal dementia with parkinsonism linked to chromosome 17 has reinforced the direct role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies. Conversely, recent data in myotonic dystrophy has demonstrated that indirect effect (CTG repeat expansion) leading to variations in tau alternative splicing also produce neurofibrillary degeneration.
- Published
- 2002
Catalog
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