Gene/Protein Disease Symptom Drug Enzyme Compound
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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 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-3beta 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 observed in AD, with a much higher frequency than in control subjects. This immunoreactivity was found to co-localize with the granulovacuolar degeneration (GVD) and to be associated with the granules of the granulovacuolar bodies. The GVD granules showed a strong GSK-3alpha and GSK-3beta immunoreactivity, and this immunoreactivity was abolished by preabsorption with recombinant GSK-3. In addition, the GVD immunoreactivity was observed with an antibody against the tyrosine-phosphorylated and active form of GSK-3. Some granules of the granulovacuolar degeneration were also intensely labeled with an antibody specific for tau isoforms containing insert 1 (exon 2) and with antibodies specific for tau phosphorylated on Ser262 and for tau phosphorylated on Thr212/Ser214, two phosphorylation sites generated in vitro by GSK-3alpha and beta. GSK-3beta was expressed in neurons containing NFT but only a small proportion of intracellular NFT were observed to be GSK-3beta immunoreactive. Immunoblotting analysis of fractions enriched in PHF-tau did not reveal any GSK-3beta immunoreactivity in these fractions, indicating that GSK-3beta was only loosely associated to NFT. These results suggest that neurons developing GVD sequester an active, potentially deleterious, form of GSK-3 in this compartment and that increased GSK-3 immunoreactivity in a subset of neurons quantitatively differentiates normal aging from AD.
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PMID:The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease. 1181 Jan 73

We report here that aggregated beta-amyloid (Abeta) 1-42 promotes tau aggregation in vitro in a dose-dependent manner. When Abeta-mediated aggregated tau was used as a substrate for tau protein kinase II (TPK II), an 8-fold increase in the rate of TPK II-mediated tau phosphorylation was observed. The extent of TPK II-dependent tau phosphorylation increased as a function of time and Abeta 1-42 concentration, and hyperphosphorylated tau was found to be decorated with an Alzheimer's disease-related phosphoepitope (P-Thr-231). In HEK 293 cells co-expressing CT-100 amyloid precursor protein and tau, the release of Abeta 1-42 from these cells was impaired. Taken together, these in vitro results suggest that Abeta 1-42 promotes both tau aggregation and hyperphosphorylation.
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PMID:Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II. 1194 63

Glycogen synthase kinase-3alpha and -3beta (GSK-3alpha and -3beta) are multi-substrate, serine/threonine-specific kinases that can phosphorylate microtubule-associated protein tau and other neuronal proteins. In this study, the expression level and mRNA distribution of two GSK-3 isoforms, GSK-3alpha and -3beta in mice were investigated. Northern blot analyses indicated that GSK-3alpha mRNA is encoded by a 2.5-kb transcript in adult tissues, whereas a 4.1-kb transcript was found in neonatal tissues. The GSK-3beta mRNA is encoded by a 1.6-kb transcript in the testis and a 7.6-kb transcript in the brain, and in many other adult tissues, but not neonatal tissues. Western blot analyses demonstrated that GSK-3beta protein was mainly expressed in the brain and heart, whereas GSK-3alpha was highly expressed in the brain, heart, and testis. A non-radioactive in situ hybridization study using specific digoxigenin-labeled RNA probes showed that GSK-3alpha and -3beta mRNAs were found in many brain regions, and were especially abundant in the hippocampus, cerebral cortex, and the Purkinje cells of the cerebellum. This implies the importance of GSK-3alpha and -3beta for brain function. The differential expression of GSK-3alpha and -3beta mRNAs as well as proteins in other tissues indicate that they play different roles in cellular functions and the developmental process.
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PMID:Expression of glycogen synthase kinase-3 isoforms in mouse tissues and their transcription in the brain. 1204 12

Pathologic alterations in the microtubule-associated protein tau have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD). Here, we show that tau overexpression, in combination with phosphorylation by the Drosophila glycogen synthase kinase-3 (GSK-3) homolog and wingless pathway component (Shaggy), exacerbated neurodegeneration induced by tau overexpression alone, leading to neurofibrillary pathology in the fly. Furthermore, manipulation of other wingless signaling molecules downstream from shaggy demonstrated that components of the Wnt signaling pathway modulate neurodegeneration induced by tau pathology in vivo but suggested that tau phosphorylation by GSK-3beta differs from canonical Wnt effects on beta-catenin stability and TCF activity. The genetic system we have established provides a powerful reagent for identification of novel modifiers of tau-induced neurodegeneration that may serve as future therapeutic targets.
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PMID:Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. 1206 36

The dissociation of the neuronal Golgi complex is a classical feature observed in neurodegenerative disorders including Alzheimer's disease. The goal of this study is to determine if the phosphorylation of tau protein is involved in neuronal Golgi disassembly. Primary cortical cultures were exposed to two Golgi toxins, brefeldin A (BFA) or nordihydroguaiaretic acid (NDGA). Immunocytochemical studies using the anti58 k antibody revealed that Golgi disassembly started in exposed neurons a few minutes after treatment. BFA and NDGA induced a rapid and transient increase in tau phosphorylation in a site-specific manner on immunoblots. In addition, the increase in tau phosphorylation directly correlated with a transient dissociation of tau from the cytoskeleton and a decrease of the acetylated tubulin. Furthermore, the activity of glycogen synthase kinase-3beta (GSK-3beta) increased transiently, as demonstrated by the kinase activity assay and by immunoblottings of serine-9 and tyrosine-216 phosphorylated of GSK-3beta. A decrease of the Akt phosphorylated form was also shown. The increase in tau phosphorylation was inhibited by the GSK-3beta inhibitor, lithium. Finally, morphometric studies showed that lithium partially blocked the Golgi disassembly caused by BFA or NDGA. Together these findings indicate that GSK-3beta activity and tau phosphorylation state are involved in the maintenance of the neuronal Golgi organization.
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PMID:Involvement of glycogen synthase kinase-3beta and tau phosphorylation in neuronal Golgi disassembly. 1206 46

Glycogen synthase kinase-3 (GSK-3) was generally considered a constitutively active enzyme, only regulated by inhibition. Here we describe that GSK-3 is activated by lysophosphatidic acid (LPA) during neurite retraction in rat cerebellar granule neurons. GSK-3 activation correlates with an increase in GSK-3 tyrosine phosphorylation. In addition, LPA induces a GSK-3-mediated hyperphosphorylation of the microtubule-associated protein tau. Inhibition of GSK-3 by lithium partially blocks neurite retraction, indicating that GSK-3 activation is important but not essential for the neurite retraction progress. GSK-3 activation by LPA in cerebellar granule neurons is neither downstream of Galpha(i) nor downstream of Galpha(q)/phospholipase C, suggesting that it is downstream of Galpha12/13. Overexpression of constitutively active Galpha12 (Galpha12QL) and Galpha13 (Galpha13QL) in Neuro2a cells induces upregulation of GSK-3 activity. Furthermore, overexpression of constitutively active RhoA (RhoAV14) also activates GSK-3 However, the activation of GSK-3 by Galpha13 is blocked by coexpression with C3 transferase, whereas C3 does not block GSK-3 activation by Galpha12. Thus, we demonstrate that GSK-3 is activated by both Galpha12 and Galpha13 in neuronal cells. However, GSK-3 activation by Galpha13 is Rho-mediated, whereas GSK-3 activation by Galpha12 is Rho-independent. The results presented here imply the existence of a previously unknown mechanism of GSK-3 activation by Galpha12/13 subunits.
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PMID:Glycogen synthase kinase-3 is activated in neuronal cells by Galpha12 and Galpha13 by Rho-independent and Rho-dependent mechanisms. 1217 84

Neurofibrillary tangles (NFTs) are found in a wide range of neurodegenerative disorders, including Alzheimer's disease. The major component of NFTs is aberrantly hyperphosphorylated microtubule-associated protein tau. Because appropriate in vivo models have been lacking, the role of tau phosphorylation in NFTs formation has remained elusive. Here, we describe a new model in which adenovirus-mediated gene expression of tau, DeltaMEKK, JNK3, and GSK-3beta in COS-7 cells produces most of the pathological phosphorylation epitopes of tau including AT100. Furthermore, this co-expression resulted in the formation of tau aggregates having short fibrils that were detergent-insoluble and Thioflavin-S-reactive. These results suggest that aberrant tau phosphorylation by the combination of these kinases may be involved in "pretangle," oligomeric tau fibril formation in vivo.
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PMID:Aberrant tau phosphorylation by glycogen synthase kinase-3beta and JNK3 induces oligomeric tau fibrils in COS-7 cells. 1219 90

Thyrotropin-releasing hormone (TRH) is best known for its hypothalamic neuroendocrine role in regulating thyroid function. In extra-hypothalamic regions in vitro, we have shown TRH to have a protective effect against synaptic loss and neuronal apoptosis. A role for TRH in Alzheimer's disease (AD) has not been established previously. In this study, we examined the content of the TRH peptide in the hippocampus of elderly controls (n=5) and AD patients (n=7) by radioimmunoassay (RIA). The TRH concentration was decreased in the AD hippocampus compared to normal elderly controls (p < 0.01). In a separate series of experiments utilizing primary cell cultures made from rat hippocampus, TRH peptide concentration was depleted by the addition of TRH antiserum. TRH withdrawal was found to enhance the activity of glycogen synthetase kinase-3 (GSK-3beta), a critical enzyme necessary for the phosphorylation of tau, as well as the phosphorylation of the tau protein itself. This TRH depletion induced upregulation in phosphorylation that was observed to initiate axonal retraction in cultured neurons. These data suggest that TRH within the hippocampus can regulate the activity of various proteins by phosphorylation/dephosphorylation that may be involved in the pathogenesis of AD.
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PMID:Thyrotropin releasing hormone (TRH) in the hippocampus of Alzheimer patients. 1221 33

Microtubule-associated protein tau is abnormally hyperphosphorylated, glycosylated, and aggregated in affected neurons in the brains of individuals with Alzheimer's disease (AD). We recently found that the glycosylation might precede hyperphosphorylation of tau in AD. In this study, we investigated the effect of glycosylation on phosphorylation of tau catalyzed by cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase-3beta (GSK-3beta). The phosphorylation of the longest isoform of recombinant human brain tau, tau(441), at various sites was detected by Western blots and by radioimmuno-dot-blot assay with phosphorylation-dependent and site-specific tau antibodies. We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. Deglycosylation by glycosidases depressed the subsequent phosphorylation of AD-tau (i) with cdk5 at Thr-181, Ser-199, Ser-202, Thr-205, and Ser-404, but not at Thr-212; and (ii) with GSK-3beta at Thr-181, Ser-202, Thr-205, Ser-217, and Ser-404, but not at Ser-199, Thr-212, Thr-231, or Ser-396. These data suggest that aberrant glycosylation of tau in AD might be involved in neurofibrillary degeneration by promoting abnormal hyperphosphorylation by cdk5 and GSK-3beta.
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PMID:Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK-3beta. 1238 94

The neuropathological features associated with Alzheimer's disease (AD) brain include the presence of extracellular neuritic plaques composed of amyloid beta protein (Abeta), intracellular neurofibrillary tangles containing phosphorylated tau protein and the loss of basal forebrain cholinergic neurons which innervate regions such as the hippocampus and the cortex. Studies of the pathological changes that characterize AD and several other lines of evidence indicate that Abeta accumulation in vivo may initiate phosphorylation of tau protein, which by disrupting neuronal network may trigger the process of neurodegeneration observed in AD brains. However, the underlying cause of degeneration of the basal forebrain cholinergic neurons and their association, if any, to Abeta peptides or phosphorylated tau remains mostly unknown. In the present study, using rat primary septal cultures, we have shown that aggregated Abeta peptides, in a time (18-96 h)- and concentration (0.7-60 microM)-dependent manner, induce toxicity and decrease choline acetyltransferase enzyme activity in cultured neurons. Using immunocytochemistry and immunoblotting, we have also demonstrated that Abeta treatment can significantly increase the phosphorylation of tau protein in septal cultures. At the cellular level, hyperphosphorylated tau is mostly apparent in the somatodendritic compartment of the neurons. Abeta peptide (10 microM), in addition to tau phosphorylation, also activates mitogen-activated protein kinase and glycogen synthase kinase-3beta, the two kinases which are known to be involved in the formation of hyperphosphorylated tau in the AD brain. Exposure to specific inhibitors of the mitogen-activated protein kinase (i.e. PD98059) or glycogen synthase kinase-3beta (i.e. LiCl) attenuated the hyperphosphorylation of the tau protein in cultured neurons. Given the evidence that tau phosphorylation can induce cell loss by disrupting neuronal cytoskeleton, it is likely that aggregated Abeta peptide triggers degeneration of septal neurons, including those expressing the cholinergic phenotype, by phosphorylation of the tau protein activated by mitogen-activated protein kinase and glycogen synthase kinase-3beta. These results, taken together, suggest that cultured septal cholinergic neurons are vulnerable to Abeta-mediated toxicity and tau phosphorylation may play an important role in Abeta-induced neurodegeneration.
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PMID:Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. 1240 34


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