Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen synthase kinase-3beta (GSK-3beta) is a multifunctional enzyme involved in a variety of biological events including development, glucose metabolism and cell death. Its activity is inhibited by phosphorylation of the Ser9 residue and up-regulated by Tyr216 phosphorylation. Activated GSK-3beta increases phosphorylation of tau protein and induces cell death in a variety of cultured neurons, whereas phosphorylation of phosphatidylinositol-3 (PI-3) kinase-dependent protein kinase B (Akt), which inhibits GSK-3beta activity, is one of the best characterized cell survival signaling pathways. In the present study, the cholinergic immunotoxin 192 IgG-saporin was used to address the potential role of GSK-3beta in the degeneration of basal forebrain cholinergic neurons, which are preferentially vulnerable in Alzheimer's disease (AD) brain. GSK-3beta co-localized with a subset of forebrain cholinergic neurons and loss of these neurons was accompanied by a transient decrease in PI-3 kinase, phospho-Ser473Akt and phospho-Ser9GSK-3beta levels, as well as an increase in phospho-tau levels, in the basal forebrain and hippocampus. Total Akt, GSK-3beta, tau and phospho-Tyr216GSK-3beta levels were not significantly altered in these brain regions in animals treated with 192 IgG-saporin. Systemic administration of the GSK-3beta inhibitor LiCl did not significantly affect cholinergic marker or phospho-Ser9GSK-3beta levels in control rats but did preclude 192-IgG saporin-induced alterations in PI-3 kinase/phospho-Akt, phospho-Ser9GSK-3beta and phospho-tau levels, and also partly protected cholinergic neurons against the immunotoxin. These results provide the first evidence that increased GSK-3beta activity, via decreased Ser9 phosphorylation, can mediate, at least in part, 192-IgG saporin-induced in vivo degeneration of forebrain cholinergic neurons by enhancing tau phosphorylation. The partial protection of these neurons following inhibition of GSK-3beta kinase activity suggests a possible therapeutic role for GSK-3beta inhibitors in attenuating the loss of basal forebrain cholinergic neurons observed in AD.
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PMID:Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser glycogen synthase kinase-3beta. 1618 30

Aberrant phosphorylated tau is the major component of the neurofibrillary tangles in Alzheimer's disease (AD) brains. Glycogen synthase kinase-3beta (GSK-3beta) phosphorylates tau protein, and increased GSK-3beta expression has been associated with neurofibrillary tangles. Saitohin (STH) is a recently identified protein that shares tissue expression pattern with tau, and previous evidence in the Spanish population indicated that a polymorphism at codon 7 (Q7R) of the STH gene was associated with late-onset AD. Since both GSK-3beta and STH are related to tau, we examined the association between a polymorphism in the promoter region (-50) of the GSK-3beta gene and AD, either through an independent effect or through interaction with the STH (Q7R) polymorphism, in a well-defined group of 333 sporadic AD patients and 307 control subjects from Spain. The current study reveals that GSK-3beta (-50) TT genotype is associated with an increased risk (OR 1.99, p = 0.003) for late-onset (after the age of 72 years) AD. Our results indicate that both the GSK-3beta (-50) and STH (Q7R) polymorphisms increase the risk of late-onset (subjects >72 years) AD, although they appear to be independent and thus not to interact synergistically.
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PMID:Association between glycogen synthase kinase-3beta genetic polymorphism and late-onset Alzheimer's disease. 1642 84

Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine kinase that is usually inactivated by serine phosphorylation in response to extracellular cues. However, GSK-3 can also be activated by tyrosine phosphorylation, but little is known about the upstream signaling events and tyrosine kinase(s) involved. Here we describe a G protein signaling pathway leading to GSK-3 activation during lysophosphatidic acid (LPA)-induced neurite retraction. Using neuronal cells expressing the LPA(1) receptor, we show that LPA(1) mediates tyrosine phosphorylation and activation of GSK-3 with subsequent phosphorylation of the microtubule-associated protein tau via the G(i)-linked PIP(2) hydrolysis-Ca(2+) mobilization pathway. LPA concomitantly activates the Ca(2+)-dependent tyrosine kinase Pyk2, which is detected in a complex with GSK-3beta. Inactivation or knockdown of Pyk2 inhibits LPA-induced (but not basal) tyrosine phosphorylation of GSK-3 and partially inhibits LPA-induced neurite retraction, similar to what is observed following GSK-3 inhibition. Thus, Pyk2 mediates LPA(1)-induced activation of GSK-3 and subsequent phosphorylation of microtubule-associated proteins. Pyk2-mediated GSK-3 activation is initiated by PIP(2) hydrolysis and may serve to destabilize microtubules during actomyosin-driven neurite retraction.
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PMID:GSK-3 is activated by the tyrosine kinase Pyk2 during LPA1-mediated neurite retraction. 1645 34

Glycogen synthase kinase-3 (GSK-3) has been proposed as the main kinase able to aberrantly phosphorylate tau in Alzheimer's disease (AD) and related tauopathies, raising the possibility of designing novel therapeutic interventions for AD based on GSK-3 inhibition. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations. Therefore, it was of great interest to test the possible protective effects of lithium in an AD animal model based on GSK-3 overexpression. We had previously generated a double transgenic model, overexpressing GSK-3beta in a conditional manner, using the Tet-off system and tau protein carrying a triple FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation. This transgenic line shows tau hyperphosphorylation in hippocampal neurones accompanied by neurofibrillary tangles (NFTs). We used this transgenic model to address two issues: first, whether chronic lithium treatment is able to prevent the formation of aberrant tau aggregates that result from the overexpression of FTDP-17 tau and GSK-3beta; second, whether lithium is able to change back already formed NFTs in aged animals. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Furthermore, it is still possible to partially reverse tau pathology in advanced stages of the disease, although NFT-like structures cannot be changed. The same results were obtained after shut-down of GSK-3beta overexpression, supporting the possibility that GSK-3 inhibition is not sufficient to reverse NFT-like aggregates.
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PMID:Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. 1705 63

Glycogen synthase kinase (GSK)-3 has been proposed as the link between the two histopathological hallmarks of Alzheimer's disease, the extracellular senile plaques made of beta-amyloid and the intracellular neurofibrillary tangles made of hyperphosphorylated tau. Thus, GSK-3 is one of the main tau kinases and it modifies several sites of tau protein present in neurofibrillary tangles. Furthermore, GSK-3 is able to modulate the generation of beta-amyloid as well as to respond to this peptide. The use of several transgenic models overexpressing GSK-3 has been associated with neuronal death, tau hyperphosphorylation and a decline in cognitive performance. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations and has been demonstrated to prevent tau phosphorylation. In this review, we summarize all these data and discuss the potential of GSK-3 inhibitors for Alzheimer's disease therapy, as well as some of their potential problems.
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PMID:GSK-3 inhibitors for Alzheimer's disease. 1799 1

Glycogen synthase kinase GSK-3beta has been identified as one of the major candidates mediating tau hyperphosphorylation at the same sites as those present in tau protein in brain from Alzheimer's disease (AD) patients. However, the signal transduction pathways involved in the abnormal activation of GSK-3beta, have not been completely elucidated. GSK-3beta activity is repressed by the canonical Wnt signaling pathway, but it is also modulated through the PI3K/Akt route. Recent studies have suggested that Wnt signaling might be involved in the pathophysiology of AD. On the other hand, modulators of the PI3K pathway might be reduced during aging leading to a sustained activation of GSK-3beta, which in turn would increase the risk of tau hyperphosphorylation. The role of Wnt and PI3K signaling inhibition on the extent of tau phosphorylation and neuronal morphology has not been completely elucidated. Thus, in the present investigation we analyzed the effects of different negative modulators of the Wnt and the PI3K pathways on GSK-3beta activation and phosphorylation of tau at the PHF-1 epitope in cortical cultured neurons and hippocampal slices from adult rat brain. Changes in the microtubule network were also studied. We found that a variety of Wnt and PI3K inhibitors, significantly increased tau phosphorylation at the PHF-1 site, induced the disarrangement of the microtubule network and the accumulation of tau within cell bodies. These changes correlated with alterations in neuronal morphology.
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PMID:Inhibition of Wnt and PI3K signaling modulates GSK-3beta activity and induces morphological changes in cortical neurons: role of tau phosphorylation. 1846 48

Glycogen synthase kinase-3beta (GSK-3beta) has been proposed as the main kinase able to phosphorylate tau aberrantly in Alzheimer's disease and in related tauopathies. We have previously generated a double transgenic mouse line overexpressing the enzyme GSK-3beta and tau protein carrying a triple frontotemporal dementia and parkinsonism linked to chromosome 17 mutation whose expression patterns overlap in CA1 (pyramidal neurons) and dentate gyrus (granular neurons). Here, we have used this transgenic model to analyze how axonal and somatodendritic neuronal compartments are affected in the hippocampus. Our data demonstrate that neuronal subpopulations respond differentially to increased GSK-3 activity. Thus, dentate gyrus granular neurons undergo apoptotic death with subsequent degeneration of the mossy fibers, while CA1 pyramidal neurons accumulate hyperphosphorylated tau both in the axonal and in the somatodendritic compartments. These studies also allow us to propose a model of spreading of pathology through the hippocampus as a consequence of GSK-3 and tau dysregulation.
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PMID:Hippocampal neuronal subpopulations are differentially affected in double transgenic mice overexpressing frontotemporal dementia and parkinsonism linked to chromosome 17 tau and glycogen synthase kinase-3beta. 1895 53

In tauopathies such as Alzheimer's disease (AD), the molecular mechanisms of tau protein aggregation into neurofibrillary tangles (NFTs) and their contribution to neurodegeneration remain not understood. It was recently demonstrated that tau, regardless of its aggregation, might represent a key mediator of neurodegeneration. Therefore, reduction of tau levels might represent a mechanism of neuroprotection. Glycogen synthase kinase-3beta (GSK3beta) and protein phosphatase-2A (PP2A) are key enzymes involved in the regulation of tau phosphorylation, and have been suggested to be involved in the abnormal tau phosphorylation and aggregation in AD. Connections between PP2A and GSK3beta signaling have been reported. We have previously demonstrated that exposure of cultured cortical neurons to lithium decreased tau protein expression and provided neuroprotection against Abeta. Since lithium is not a specific inhibitor of GSK3beta (ID50=2.0 mM), whether or not the lithium-induced tau decrease involves GSK3beta remained to be determined. For that purpose, cultured cortical neurons were exposed to 6-bromo-indirubin-3'-oxime (6-BIO), a more selective and potent GSK3beta inhibitor (ID50=1.5 microM) or to lithium. Analysis of tau levels and phosphorylation by western-blot assays showed that lithium and 6-BIO dose-dependently decreased both tau protein levels and tau phosphorylation. Conversely, inhibition of cyclin-dependent kinase-5 (CDK5) by roscovitine decreased phosphorylated tau but failed to alter tau protein levels. These data indicate that GSK3beta might be selectively involved in the regulation of tau protein levels. Moreover, inhibition of PP2A by okadaic acid, but not that of PP2B (protein phosphatase-2B)/calcineurin by FK506, dose-dependently reversed lithium-induced tau decrease. These data indicate that GSK3beta regulates both tau phosphorylation and total tau levels through PP2A.
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PMID:Inhibition of glycogen synthase kinase-3beta downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A. 1907 Oct 93

Glycogen synthase kinase-3beta (GSK-3beta) is implicated in abnormal hyperphosphorylation of tau protein and its inhibitors are expected to be a promising therapeutic agents for the treatment of Alzheimer's disease. Here we report design, synthesis and structure-activity relationships of a novel series of oxadiazole derivatives as GSK-3beta inhibitors. Among these inhibitors, compound 20x showed highly selective and potent GSK-3beta inhibitory activity in vitro and its binding mode was determined by obtaining the X-ray co-crystal structure of 20x and GSK-3beta.
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PMID:Design, synthesis and structure-activity relationships of 1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3beta. 1920 Jul 45

Glycogen synthase kinase 3 (GSK3), a constitutively acting multi-functional serine threonine kinase is involved in diverse physiological pathways ranging from metabolism, cell cycle, gene expression, development and oncogenesis to neuroprotection. These diverse multiple functions attributed to GSK3 can be explained by variety of substrates like glycogen synthase, tau protein and beta catenin that are phosphorylated leading to their inactivation. GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. GSK3 negatively regulates insulin-mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. Consequently, inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in vitro and in animal models. However, inhibition of GSK3 poses a challenge as achieving selectivity of an over achieving kinase involved in various pathways with multiple substrates may lead to side effects and toxicity. The primary concern is developing inhibitors of GSK3 that are anti-diabetic but do not lead to up-regulation of oncogenes. The focus of this review is the recent advances and the challenges surrounding GSK3 as an anti-diabetic therapeutic target.
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PMID:Glycogen synthase kinase 3: more than a namesake. 1936 50


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