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Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration.

Published on Dec 1, 2002in Acta Neuropathologica18.17
· DOI :10.1007/s00401-002-0587-8
Isidre Ferrer72
Estimated H-index: 72
,
Marta Barrachina27
Estimated H-index: 27
(University of Barcelona),
B. Puig26
Estimated H-index: 26
(University of Barcelona)
Cite
Abstract
Tau phosphorylation was examined in Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) using phospho-specific tau antibodies recognizing the phosphorylated form of Ser202, Ser214 and Ser 396, and antibodies to non-phosphorylated glycogen synthase kinase-3α/β (GSK-3α/β), which regulates phosphorylation at these specific sites on tau and phosphorylated GSK-3βSer9 (GSK-3β-P); this antibody is directed to the inactive form of GSK-3β. Phospho-specific tau antibodies recognized disease-specific band patterns on Western blots of sarcosyl-insoluble fractions: four bands of 73, 68, 64 and 60 kDa in AD, two bands of 68 and 64 kDa in PSP and CBD, and two bands of 64 and 60 kDa in PiD. Moreover, anti-phospho-tau Ser202, Ser214 and Ser369 decorated neurons with neurofibrillary tangles, dystrophic neurites of senile plaques, neuropil threads, Pick bodies, astrocytes and oligodendrocytes with coiled bodies. No differences in the expression of GSK-3α/β were seen between neurons with and without neurofibrillary tangles. GSK-3α/β was enriched in sarcosyl-insoluble fractions, suggesting association of this kinase with tau hyperphosphorylation. In addition, strong expression of the phosphorylated form of GSK-3β was found in a subpopulation of neurons with neurofibrillary tangles, and in dystrophic neurites of senile plaques, neuropil threads, Pick bodies, tau-containing astrocytes and coiled bodies in AD, PiD, PSP and CBD. This was not due to cross-reactivity between GSK-3 and phospho-tau. Specific bands differing from those of phospho-tau were seen on Western blots of sarcosyl-insoluble fractions processed for GSK-3α/β and GSK-3β-P. Double-labeling immunohistochemistry discloses that GSK-3β-P co-localizes with abnormal tau in about 50% of neurons with neurofibrillary tangles, and in neuronal processes, astrocytes and oligodendrocytes in various tauopathies. The present results support a pivotal role for GSK-3 in tau phosphorylation in neurons and glial cells. Moreover, the elevated number of tau-containing cells stained with anti-GSK-3β-P antibodies suggests a partial inactivation of the kinase, or sequestration of the phosphorylated form, which may contribute to the regulation of the cascade of tau hyperphosphorylation in tauopathies, and to protect tau-containing cells from apoptosis.
  • References (38)
  • Citations (127)
Cite
References38
Newest
Published on Apr 5, 2006in Brain Pathology6.16
Isidre Ferrer72
Estimated H-index: 72
(University of Barcelona),
R. Blanco15
Estimated H-index: 15
+ 7 AuthorsTeresa Ribalta28
Estimated H-index: 28
(University of Barcelona)
Abnormal tau phosphorylation and deposition in neurones and glial cells is one of the major features in tau pathies. The present study examines the involvement of the Ras/MEK/ERK pathway of tau phosphorylation in Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), by Western blotting, single and double-labelling immunohistochemistry, and p21Ras activation assay. Since this pathway is also activated in several paradigms of cell d...
Published on Feb 1, 2002in Acta Neuropathologica18.17
Karelle Leroy25
Estimated H-index: 25
(ULB: Université libre de Bruxelles),
Allal Boutajangout5
Estimated H-index: 5
(ULB: Université libre de Bruxelles)
+ 3 AuthorsJean Pierre Brion52
Estimated H-index: 52
(ULB: Université libre de Bruxelles)
Glycogen synthase kinase-3β (GSK-3β) is a physiological kinase for tau and is a candidate protein kinase involved in the hyperphosphorylation of tau present in paired helical filament (PHF)-tau of neurofibrillary tangles (NFT) in Alzheimer's disease (AD). GSK-3β is also a key element of several signaling cascades (including cell death cascades). We have investigated the immunocytochemical localization of GSK-3 immunoreactivity in AD. Neurons exhibiting strongly GSK-3-immunoreactive granules were...
Published on Jan 18, 2002in Journal of Neurochemistry4.87
Christopher Hugh Reynolds1
Estimated H-index: 1
,
Joanna Betts15
Estimated H-index: 15
+ 2 AuthorsBrian H. Anderton65
Estimated H-index: 65
The stress-activated kinases c-Jun N-terminal kinase (JNK) and p38 are members of the mitogen-activated protein (MAP) kinase family and take part in signalling cascades initiated by various forms of stress. Their targets include the microtubule-associated protein tau, which becomes hyperphosphorylated in Alzheimer's disease. It is necessary, as a forerunner for in vivo studies, to identify the protein kinases and phosphatases that are responsible for phosphate turnover at individual sites. Using...
Published on Dec 1, 2001in Journal of Neural Transmission2.90
Isidre Ferrer72
Estimated H-index: 72
,
R. Blanco15
Estimated H-index: 15
(University of Barcelona)
+ 1 AuthorsB. Puig26
Estimated H-index: 26
(University of Barcelona)
Calcium/calmodulin-dependent kinase II (α- and β-CaM kinase II), and phosphorylated mitogen-activated extracellular signal-regulated protein kinase (MAPK/ERK-P), phosphorylated protein kinase of 38 kDa (p38-P) and phosphorylated stress-activated protein kinase (SAPK/JNK-P) expression have been examined in Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The study was carried out to increase understanding of the signals that m...
Published on Dec 1, 2001in Journal of Neuropathology and Experimental Neurology3.46
Cristiana Atzori9
Estimated H-index: 9
,
Bernardino Ghetti80
Estimated H-index: 80
+ 5 AuthorsAntonio Migheli39
Estimated H-index: 39
(UNITO: University of Turin)
JNK and p38, two members of the MAP kinase family, are strongly induced by various stresses including oxidative stress and have been involved in regulation of apoptosis. As both kinases phosphorylate tau protein in vitro, we have investigated their immunohistochemical localization in a group of neurodegenerative diseases characterized by intracellular deposits of hyperphosphorylated tau. Cases included Alzheimer disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, Ge...
Published on Oct 1, 2001in Nature Reviews Molecular Cell Biology43.35
Philip Cohen130
Estimated H-index: 130
(Dund.: University of Dundee),
Sheelagh Frame14
Estimated H-index: 14
Glycogen synthase kinase 3 (GSK3) was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate a diverse array of cell functions. The study of the substrate specificity and regulation of GSK3 activity has been important in the quest for therapeutic intervention.
Published on Jun 1, 2001in Molecular Cell14.55
Sheelagh Frame14
Estimated H-index: 14
(Dund.: University of Dundee),
Philip Cohen130
Estimated H-index: 130
(Dund.: University of Dundee),
Ricardo M. Biondi25
Estimated H-index: 25
(Dund.: University of Dundee)
Abstract The inhibition of GSK3 is required for the stimulation of glycogen and protein synthesis by insulin and the specification of cell fate during development. Here, we demonstrate that the insulin-induced inhibition of GSK3 and its unique substrate specificity are explained by the existence of a phosphate binding site in which Arg-96 is critical. Thus, mutation of Arg-96 abolishes the phosphorylation of "primed" glycogen synthase as well as inhibition by PKB-mediated phosphorylation of Ser-...
Published on Apr 1, 2001in Journal of Neurochemistry4.87
Darren A.E. Cross2
Estimated H-index: 2
(GSK: GlaxoSmithKline),
Ainsley A. Culbert9
Estimated H-index: 9
(GSK: GlaxoSmithKline)
+ 3 AuthorsAlastair D. Reith17
Estimated H-index: 17
(GSK: GlaxoSmithKline)
The phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (PKB; also known as Akt) signalling pathway is recognized as playing a central role in the survival of diverse cell types. Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine protein kinase that is one of several known substrates of PKB. PKB phosphorylates GSK-3 in response to insulin and growth factors, which inhibits GSK-3 activity and leads to the modulation of multiple GSK-3 regulated cellular proces...
Published on Jan 15, 2001in The EMBO Journal11.23
José J. Lucas5
Estimated H-index: 5
(Columbia University),
Félix Hernández41
Estimated H-index: 41
(Columbia University)
+ 3 AuthorsJesús Avila71
Estimated H-index: 71
(CSIC: Spanish National Research Council)
Glycogen synthase kinase‐3β (GSK‐3β) has been postulated to mediate Alzheimer9s disease tau hyperphosphorylation, β‐amyloid‐induced neurotoxicity and presenilin‐1 mutation pathogenic effects. By using the tet‐regulated system we have produced conditional transgenic mice overexpressing GSK‐3β in the brain during adulthood while avoiding perinatal lethality due to embryonic transgene expression. These mice show decreased levels of nuclear β‐catenin and hyperphosphorylation of tau in hippocampal ne...
Published on Jan 1, 2001in Journal of Neurochemistry4.87
Xiongwei Zhu82
Estimated H-index: 82
(Case Western Reserve University),
Arun K. Raina35
Estimated H-index: 35
(Case Western Reserve University)
+ 4 AuthorsMark A. Smith119
Estimated H-index: 119
(Case Western Reserve University)
Cellular responses to increased oxidative stress appear to be a mechanism that contributes to the varied cytopathology of Alzheimer's disease (AD). In this regard, we suspect that c-Jun N-terminal kinase/Stress activated protein kinase (JNK/SAPK), a major cellular stress response protein induced by oxidative stress, plays an important role in Alzheimer disease in susceptible neurons facing the dilemma of proliferation or death. We found that JNK2/SAPK-α and JNK3/SAPK-β were related to neurofibri...
Cited By127
Newest
Published on Dec 1, 2019in Acta neuropathologica communications
Marta Garcia-Montojo1
Estimated H-index: 1
(NIH: National Institutes of Health),
Wenxue Li11
Estimated H-index: 11
(NIH: National Institutes of Health),
Avindra Nath33
Estimated H-index: 33
(NIH: National Institutes of Health)
Published on Jun 1, 2019in Progress in Neurobiology10.66
Thomas W. Rösler2
Estimated H-index: 2
(TUM: Technische Universität München),
Amir Tayaranian Marvian (TUM: Technische Universität München)+ 15 AuthorsK. Schweyer (TUM: Technische Universität München)
Abstract Tau is a microtubule-associated protein with versatile functions in the dynamic assembly of the neuronal cytoskeleton. Four-repeat (4R-) tauopathies are a group of neurodegenerative diseases defined by cytoplasmic inclusions predominantly composed of tau protein isoforms with four microtubule-binding domains. Progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease or glial globular tauopathy belong to the group of 4R-tauopathies. The present review provides...
Published on Jun 1, 2019in Neurobiology of Aging4.40
Luc Poncelet14
Estimated H-index: 14
(ULB: Université libre de Bruxelles),
Kunie Ando16
Estimated H-index: 16
(ULB: Université libre de Bruxelles)
+ 7 AuthorsKarelle Leroy25
Estimated H-index: 25
(ULB: Université libre de Bruxelles)
Abstract Human tauopathies are neurodegenerative diseases with accumulation of abnormally phosphorylated and aggregated tau proteins forming neurofibrillary tangles (NFT). We investigated the development of tau pathology in aged cat brains as a model of NFT formation occurring spontaneously during aging. In 4 out of 6 cats aged between 18 and 21 years, we found a somatodendritic accumulation of phosphorylated and aggregated tau in neurons and oligodendrocytes. Two of these 4 cats had no amyloid ...
Published on Jul 8, 2019in Movement Disorders8.06
Maria Stamelou29
Estimated H-index: 29
(UoA: National and Kapodistrian University of Athens),
Nikolaos Giagkou1
Estimated H-index: 1
,
Günter U. Höglinger34
Estimated H-index: 34
(TUM: Technische Universität München)
Published on Apr 26, 2019in Current Enzyme Inhibition
Satya P. Gupta5
Estimated H-index: 5
(Meerut Institute of Engineering and Technology)
Published on Mar 1, 2019in Neurobiology of Aging4.40
Robert A. Whittington19
Estimated H-index: 19
(Columbia University),
Laszlo Virag14
Estimated H-index: 14
(Columbia University)
+ 6 AuthorsEmmanuel Planel25
Estimated H-index: 25
(Laval University)
Abstract Preclinical studies have shown that anesthesia might accelerate the clinical progression of Alzheimer's disease (AD) and can have an impact on tau pathology, a hallmark of AD. Although benzodiazepines have been suggested to increase the risk of incident dementia, their impact on tau pathology in vivo is unknown. We thus examined the impact of midazolam, a benzodiazepine that is often administered perioperatively as an anxiolytic, on tau hyperphosphorylation in nontransgenic and in hTau ...
Published on Feb 1, 2019in Parkinsonism & Related Disorders4.36
Nahid Olfati2
Estimated H-index: 2
(MUMS: Mashhad University of Medical Sciences),
Ali Shoeibi7
Estimated H-index: 7
(MUMS: Mashhad University of Medical Sciences),
Irene Litvan77
Estimated H-index: 77
(UCSD: University of California, San Diego)
Abstract Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) are the four major proteinopathic neurodegenerative disorders. Currently, there are no disease modifying therapies for these disorders. However, better understanding of the etiopathogenic mechanisms of these disorders has allowed the development of novel therapeutic approaches. These mainly include strategies directed to the pathologic conformational ...
Published on Jan 1, 2019in Neurobiology of Aging4.40
Linyu Zhang1
Estimated H-index: 1
(ECNU: East China Normal University),
Hao Dong1
Estimated H-index: 1
(ECNU: East China Normal University)
+ 4 AuthorsBo Meng1
Estimated H-index: 1
(ECNU: East China Normal University)
Abstract MicroRNAs, small noncoding RNAs, not only regulate gene expression at the post-transcriptional level in a variety of physiological processes but also accompany the initiation and progression of a vast number of diseases, including dementia. While miR-125b has been shown to be aberrantly expressed in some dementia patients, its role in the pathological process remains ambiguous. Presenilin-1/2 conditional double knockout mice exhibit a range of symptoms, including impaired cognition and ...
Published on Dec 26, 2018
Abdalla M. Albeely (U of G: University of Guelph), Scott D. Ryan5
Estimated H-index: 5
(U of G: University of Guelph)
+ 0 AuthorsMelissa L. Perreault15
Estimated H-index: 15
(U of G: University of Guelph)
Published on Oct 1, 2018in Progress in Neurobiology10.66
Isidro Ferrer57
Estimated H-index: 57
Abstract Oligodendrocytes are in contact with neurons, wrap axons with a myelin sheath that protects their structural integrity, and facilitate nerve conduction. Oligodendrocytes also form a syncytium with astrocytes which interacts with neurons, promoting reciprocal survival mediated by activity and by molecules involved in energy metabolism and trophism. Therefore, oligodendrocytes are key elements in the normal functioning of the central nervous system. Oligodendrocytes are affected following...