The Experts below are selected from a list of 582 Experts worldwide ranked by ideXlab platform
Michel Goedert - One of the best experts on this subject based on the ideXlab platform.
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tau protein the Paired Helical Filament and alzheimer s disease
Journal of Alzheimer's Disease, 2006Co-Authors: Michel Goedert, Aaron Klug, Anthony R CrowtherAbstract:In 1906, Alzheimer described the clinical and neuropathological characteristics of the disease that was subsequently named after him. Although the Paired Helical Filament was identified as the major component of the neu- rofibrillary pathology of Alzheimer's disease in 1963, its molecular composi- tion was only uncovered in the 1980s. In 1988, work at the MRC Laboratory of Molecular Biology in Cambridge (UK) provided direct proof that tau protein is an integral component of the Paired Helical Filament. The paper highlighted here (Goedert M., Wischik C.M., Crowther R.A., Walker J.E. and Klug A. (1988) Cloning and sequencing of a core protein of the Paired Helical Filament of Alzheimer disease: Identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. USA 85, 4051-4055) also reported the first sequence of a human tau isoform and paved the way for the identification of the six brain tau isoforms that are expressed by alternative mRNA splicing from a single gene. By the early 1990s, it was clear that tau protein is the major component of the Paired Helical Filament and that the latter is made of all six tau isoforms, each full-length and hyperphosphorylated.
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mutations in the tau gene mapt in ftdp 17 the family with multiple system tauopathy with presenile dementia mstd
Journal of Alzheimer's Disease, 2006Co-Authors: Maria Grazia Spillantini, Michel Goedert, Aaron Klug, Jill R Murrell, Martin R Farlow, Bernardino GhettiAbstract:Work in 1980s and early 1990s established that the microtubule- associated protein tau is the major component of the Paired Helical Filament of Alzheimer's disease. Similar Filamentous deposits are also present in a number of other diseases, including progressive supranuclear palsy,corticobasal degeneration and Pick's disease. In 1998, the relevance of tau dysfunction for the neurodegenerative process became clear, when mutations in the tau gene were found to cause the inherited "frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)." The paper highlighted here (Spillantini M.G., Murrell J.R., Goedert M., Farlow M., Klug A. and Ghetti B. (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95, 7737-7741) reported a mutation at position +3 in the intron following alternatively spliced exon 10 of the tau gene in a family with abundant Filamentous deposits made exclusively of four-repeat tau. Levels of soluble four-repeat tau were increased in individuals with this mutation. It was proposed that the +3 mutation destabilises a stem-loop structure located at the end of exon 10 and the beginning of the intron, thus resulting in an abnormal ratio of three-repeat to four-repeat tau isoforms.
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protein phosphatase 2a is the major enzyme in brain that dephosphorylates τ protein phosphorylated by proline directed protein kinases or cyclic amp dependent protein kinase
Journal of Neurochemistry, 2002Co-Authors: Michel Goedert, R Jakes, J H WangAbstract:The Paired Helical Filament (PHF), which makes up the major fibrous component of the neurofibrillary lesions of Alzheimer's disease, is composed of hyperphosphorylated and abnormally phosphorylated microtubule-associated protein tau. Previous studies have identified serine and threonine residues phosphorylated in PHF-tau and have shown that tau can be phosphorylated at several of these sites by proline-directed protein kinases and cyclic AMP-dependent protein kinase. Here we have investigated which protein phosphatase activities can dephosphorylate recombinant tau phosphorylated with mitogen-activated protein kinase, glycogen synthase kinase-3 beta, neuronal cdc2-like kinase, or cyclic AMP-dependent protein kinase. We show that protein phosphatase 2A is by far the major protein phosphatase activity in brain that dephosphorylates tau phosphorylated in this manner.
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phosphorylation of microtubule associated protein tau by stress activated protein kinases
FEBS Letters, 1997Co-Authors: Michel Goedert, R Jakes, Masato Hasegawa, Sean E Lawler, Ana Cuenda, Philip CohenAbstract:The Paired Helical Filament, which comprises the major fibrous element of the neurofibrillary lesions of Alzheimer's disease, is composed of hyperphosphorylated microtubule-associated protein tau. Many of the hyperphosphorylated sites in tau are serine/threonine-prolines. Here we show that the stress-activated protein (SAP) kinases SAPK1γ (also called JNK1), SAPK2a (also called p38, RK, CSBPs, Mpk2 and Mxi2), SAPK2b (also called p38β), SAPK3 (also called ERK6 and p38γ) and SAPK4 phosphorylate tau at many serine/threonine-prolines, as assessed by the generation of the epitopes of phosphorylation-dependent anti-tau antibodies. Based on initial rates of phosphorylation, tau was found to be a good substrate for SAPK4 and SAPK3, a reasonable substrate for SAPK2b and a relatively poor substrate for SAPK2a and SAPK1γ. Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in its ability to promote microtubule assembly. These findings double the number of candidate protein kinases for the hyperphosphorylation of tau in Alzheimer's disease and other neurodegenerative disorders.
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assembly of microtubule associated protein tau into alzheimer like Filaments induced by sulphated glycosaminoglycans
Nature, 1996Co-Authors: Michel Goedert, R Jakes, Maria Grazia Spillantini, Masato Hasegawa, Michael J Smith, R A CrowtherAbstract:The Paired Helical Filament (PHF) is the major component of the neurofibrillary deposits that form a defining neuropathological characteristic of Alzheimer's disease. PHFs are composed of microtubule-associated protein tau, in a hyperphosphorylated state. Hyperphosphorylation of tau results in its inability to bind to microtubules and is believed to precede PHF assembly. However, it is unclear whether hyperphosphorylation of tau is either necessary or sufficient for PHF formation. Here we show that non-phosphorylated recombinant tau isoforms with three microtubule-binding repeats form Paired Helical-like Filaments under physiological conditions in vitro, when incubated with sulphated glycosaminoglycans such as heparin or heparan sulphate. Furthermore, heparin prevents tau from binding to microtubules and promotes microtubule disassembly. Finally, we show that heparan sulphate and hyperphosphorylated tau coexist in nerve cells of the Alzheimer's disease brain at the earliest known stages of neurofibrillary pathology. These findings, with previous studies which show that heparin stimulates tau phosphorylation by a number of protein kinases, indicate that sulphated glycosaminoglycans may be a key factor in the formation of the neurofibrillary lesions of Alzheimer's disease.
R Jakes - One of the best experts on this subject based on the ideXlab platform.
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protein phosphatase 2a is the major enzyme in brain that dephosphorylates τ protein phosphorylated by proline directed protein kinases or cyclic amp dependent protein kinase
Journal of Neurochemistry, 2002Co-Authors: Michel Goedert, R Jakes, J H WangAbstract:The Paired Helical Filament (PHF), which makes up the major fibrous component of the neurofibrillary lesions of Alzheimer's disease, is composed of hyperphosphorylated and abnormally phosphorylated microtubule-associated protein tau. Previous studies have identified serine and threonine residues phosphorylated in PHF-tau and have shown that tau can be phosphorylated at several of these sites by proline-directed protein kinases and cyclic AMP-dependent protein kinase. Here we have investigated which protein phosphatase activities can dephosphorylate recombinant tau phosphorylated with mitogen-activated protein kinase, glycogen synthase kinase-3 beta, neuronal cdc2-like kinase, or cyclic AMP-dependent protein kinase. We show that protein phosphatase 2A is by far the major protein phosphatase activity in brain that dephosphorylates tau phosphorylated in this manner.
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phosphorylation of microtubule associated protein tau by stress activated protein kinases
FEBS Letters, 1997Co-Authors: Michel Goedert, R Jakes, Masato Hasegawa, Sean E Lawler, Ana Cuenda, Philip CohenAbstract:The Paired Helical Filament, which comprises the major fibrous element of the neurofibrillary lesions of Alzheimer's disease, is composed of hyperphosphorylated microtubule-associated protein tau. Many of the hyperphosphorylated sites in tau are serine/threonine-prolines. Here we show that the stress-activated protein (SAP) kinases SAPK1γ (also called JNK1), SAPK2a (also called p38, RK, CSBPs, Mpk2 and Mxi2), SAPK2b (also called p38β), SAPK3 (also called ERK6 and p38γ) and SAPK4 phosphorylate tau at many serine/threonine-prolines, as assessed by the generation of the epitopes of phosphorylation-dependent anti-tau antibodies. Based on initial rates of phosphorylation, tau was found to be a good substrate for SAPK4 and SAPK3, a reasonable substrate for SAPK2b and a relatively poor substrate for SAPK2a and SAPK1γ. Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in its ability to promote microtubule assembly. These findings double the number of candidate protein kinases for the hyperphosphorylation of tau in Alzheimer's disease and other neurodegenerative disorders.
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Two-dimensional characterization of Paired Helical Filament-tau from Alzheimer’s disease: demonstration of an additional 74-kDa component and age-related biochemical modifications
1997Co-Authors: N. Sergeant, R Jakes, -p. J. David, M. Goedert, P. Vermersch, L. Buée, D. Lefranc, A. Wattez, A. DelacourteAbstract:Abstract: PHF-tau proteins are the major components of the Paired Helical Filament (PHF) from Alzheimer‘s disease (AD) neurofibrillary lesions. They differ both qualitatively and quantitatively in their degree of phosphorylation when compared with native tau proteins. However, little is known about the extent and heterogeneity of phos-phorylated sites or the isoform composition and the iso-electric variants of PHF-tau. Therefore, we have charac-terized PHF-tau proteins from cortical brain tissue ho-mogenates of 13 AD patients using two-dimensional gel electrophoresis. Whatever the topographical origin of brain tissue homogenates, PHF-tau proteins shared the same two-dimensional gel electrophoresis profile made of a tau triplet of 55, 64, and 69 kDa. A 74-kDa hyperphos-phorylated tau component was detected particularly i
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assembly of microtubule associated protein tau into alzheimer like Filaments induced by sulphated glycosaminoglycans
Nature, 1996Co-Authors: Michel Goedert, R Jakes, Maria Grazia Spillantini, Masato Hasegawa, Michael J Smith, R A CrowtherAbstract:The Paired Helical Filament (PHF) is the major component of the neurofibrillary deposits that form a defining neuropathological characteristic of Alzheimer's disease. PHFs are composed of microtubule-associated protein tau, in a hyperphosphorylated state. Hyperphosphorylation of tau results in its inability to bind to microtubules and is believed to precede PHF assembly. However, it is unclear whether hyperphosphorylation of tau is either necessary or sufficient for PHF formation. Here we show that non-phosphorylated recombinant tau isoforms with three microtubule-binding repeats form Paired Helical-like Filaments under physiological conditions in vitro, when incubated with sulphated glycosaminoglycans such as heparin or heparan sulphate. Furthermore, heparin prevents tau from binding to microtubules and promotes microtubule disassembly. Finally, we show that heparan sulphate and hyperphosphorylated tau coexist in nerve cells of the Alzheimer's disease brain at the earliest known stages of neurofibrillary pathology. These findings, with previous studies which show that heparin stimulates tau phosphorylation by a number of protein kinases, indicate that sulphated glycosaminoglycans may be a key factor in the formation of the neurofibrillary lesions of Alzheimer's disease.
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assembly of microtubule associated protein tau into alzheimer like Filaments induced by sulphated glycosaminoglycans
Nature, 1996Co-Authors: Michel Goedert, R Jakes, Maria Grazia Spillantini, Masato Hasegawa, Michael Smith, R A CrowtherAbstract:THE Paired Helical Filament (PHF) is the major component of the neurofibrillary deposits that form a defining neuropathological characteristic of Alzheimer's disease (reviewed in refs 1,2). PHFs are composed of micro tubule-associated protein tau, in a hyper-phosphorylated state3–8. Hyperphosphorylation of tau results in its inability to bind to microtubules9,10 and is believed to precede PHF assembly11. However, it is unclear whether hyperphosphor-ylation of tau is either necessary or sufficient for PHF formation. Here we show that non-phosphorylated recombinant tau iso-forms with three microtubule-binding repeats form Paired Helical-like Filaments under physiological conditions in vitro, when incubated with sulphated glycosaminoglycans such as heparin or heparan sulphate. Furthermore, heparin prevents tau from binding to microtubules and promotes microtubule disassembly. Finally, we show that heparan sulphate and hyperphosphorylated tau coexist in nerve cells of the Alzheimer's disease brain at the earliest known stages of neurofibrillary pathology. These findings, with previous studies which show that heparin stimulates tau phosphorylation by a number of protein kinases12–14, indicate that sulphated glycosaminoglycans may be a key factor in the formation of the neurofibrillary lesions of Alzheimer's disease.
Nikolaus D Obholzer - One of the best experts on this subject based on the ideXlab platform.
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association of brain dna methylation in sorl1 abca7 hla drb5 slc24a4 and bin1 with pathological diagnosis of alzheimer disease
JAMA Neurology, 2015Co-Authors: Lori B Chibnik, Gyan Srivastava, Nathalie Pochet, Jingyun Yang, James Kozubek, Nikolaus D ObholzerAbstract:Importance Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown. Objective To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies. Design, Setting, and Participants Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old. Exposures DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay. Main Outcomes and Measures Pathological diagnosis of AD by National Institute on Aging–Reagan criteria following a standard postmortem examination. Results Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1 , ABCA7 , HLA-DRB5 , SLC24A4 , and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and Paired Helical Filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with Paired Helical Filament tau tangle density, and the expression of BIN1 was associated with Aβ load. Conclusions and Relevance Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.
James Kozubek - One of the best experts on this subject based on the ideXlab platform.
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association of brain dna methylation in sorl1 abca7 hla drb5 slc24a4 and bin1 with pathological diagnosis of alzheimer disease
JAMA Neurology, 2015Co-Authors: Lei Yu, Lori B Chibnik, Gyan Srivastava, Nathalie Pochet, Jingyun Yang, Jishu Xu, James KozubekAbstract:Importance Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown. Objective To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies. Design, Setting, and Participants Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old. Exposures DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay. Main Outcomes and Measures Pathological diagnosis of AD by National Institute on Aging–Reagan criteria following a standard postmortem examination. Results Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1 , ABCA7 , HLA-DRB5 , SLC24A4 , and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and Paired Helical Filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with Paired Helical Filament tau tangle density, and the expression of BIN1 was associated with Aβ load. Conclusions and Relevance Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.
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association of brain dna methylation in sorl1 abca7 hla drb5 slc24a4 and bin1 with pathological diagnosis of alzheimer disease
JAMA Neurology, 2015Co-Authors: Lori B Chibnik, Gyan Srivastava, Nathalie Pochet, Jingyun Yang, James Kozubek, Nikolaus D ObholzerAbstract:Importance Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown. Objective To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies. Design, Setting, and Participants Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old. Exposures DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay. Main Outcomes and Measures Pathological diagnosis of AD by National Institute on Aging–Reagan criteria following a standard postmortem examination. Results Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1 , ABCA7 , HLA-DRB5 , SLC24A4 , and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and Paired Helical Filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with Paired Helical Filament tau tangle density, and the expression of BIN1 was associated with Aβ load. Conclusions and Relevance Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.
Gyan Srivastava - One of the best experts on this subject based on the ideXlab platform.
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association of brain dna methylation in sorl1 abca7 hla drb5 slc24a4 and bin1 with pathological diagnosis of alzheimer disease
JAMA Neurology, 2015Co-Authors: Lei Yu, Lori B Chibnik, Gyan Srivastava, Nathalie Pochet, Jingyun Yang, Jishu Xu, James KozubekAbstract:Importance Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown. Objective To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies. Design, Setting, and Participants Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old. Exposures DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay. Main Outcomes and Measures Pathological diagnosis of AD by National Institute on Aging–Reagan criteria following a standard postmortem examination. Results Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1 , ABCA7 , HLA-DRB5 , SLC24A4 , and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and Paired Helical Filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with Paired Helical Filament tau tangle density, and the expression of BIN1 was associated with Aβ load. Conclusions and Relevance Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.
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association of brain dna methylation in sorl1 abca7 hla drb5 slc24a4 and bin1 with pathological diagnosis of alzheimer disease
JAMA Neurology, 2015Co-Authors: Lori B Chibnik, Gyan Srivastava, Nathalie Pochet, Jingyun Yang, James Kozubek, Nikolaus D ObholzerAbstract:Importance Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown. Objective To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies. Design, Setting, and Participants Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old. Exposures DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay. Main Outcomes and Measures Pathological diagnosis of AD by National Institute on Aging–Reagan criteria following a standard postmortem examination. Results Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1 , ABCA7 , HLA-DRB5 , SLC24A4 , and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and Paired Helical Filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with Paired Helical Filament tau tangle density, and the expression of BIN1 was associated with Aβ load. Conclusions and Relevance Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.
