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)

Hyperphosphorylated forms of the microtubule-associated protein tau are components of the paired helical filaments (PHFs) seen in patients with Alzheimer's disease. Slices of human lateral temporal cortex were obtained from tissues removed incidental to resections for intractable hippocampal epilepsy. Tau phosphorylation in temporal lobe slices was determined using mobility shifts after sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunodetection with the monoclonal antibodies Alz-50, 5E2, and Tau-1. The results indicate that tau phosphorylation was altered in a dose-dependent manner by the phosphatase inhibitor okadaic acid, but not by N-methyl-D-aspartate, quisqualate, or kainate. The slowest mobility forms of tau, termed "PHF-like tau," produced by okadaic acid treatment were dephosphorylated by purified protein phosphatase 2B (calcineurin). Formation of PHF-like tau peptides was blocked by KN-62, 1[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazi ne, an inhibitor of Ca2+/calmodulin-dependent protein kinase II. The protein kinase inhibitor staurosporine also prevented formation of PHF-like tau. These data suggest that phosphorylation of tau is regulated by Ca(2+)-dependent protein kinases and okadaic acid-sensitive protein phosphatases, alterations of which may be implicated in the pathogenesis of Alzheimer's disease.
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PMID:Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices. 849 35

Previous studies have shown that treating rat cortical neurons in primary culture with apolipoprotein E (apoE) peptide increased cytoplasmic Ca2+ by 2 mechanisms: 1) an influx of extracellular Ca2+ resulting from the activation of a cell surface Ca2+ channel; and 2) release of Ca2+ from internal Ca2+ stores via a G-protein-coupled pathway (Wang and Gruenstein, 1997). These studies employed a biologically active apoE synthetic peptide (apoEdp) derived from the receptor binding domain of apoE. In the present study we examined whether activation of these 2 signal transduction pathways affects phosphorylation of microtubule-associated protein tau. The levels of tau phosphorylation at thr231, ser235, and ser396 were quantified by ELISA employing monoclonal antibodies PHF-6, SMI33, and PHF-1. ApoEdp treatment resulted in a concentration- and time-dependent dephosphorylation of tau at all 3 phosphorylation sites. The apoEdp-induced dephosphorylation of tau at thr231, and ser235 was dependent on the influx of extracellular Ca2+, while dephosphorylation at ser396 was mediated by a pertusis toxin-sensitive G-protein pathway. The involvement of protein phosphatases in mediating the apoEdp-induced dephosphorylation of tau was examined. Pretreatment with the protein phosphatase 2B inhibitor cyclosporin A blocked the apoEdp-induced dephosphorylation of tau at thr231 and ser235 but not at ser396. Pretreatment with the protein phosophatase 2A/1 inhibitor okadaic acid blocked the apoEdp-induced dephosphorylation of tau at all 3 sites, while pretreatment with the protein phosphates 1 inhibitor tautomycin was without effect. The present study suggests that apoE may affect several Ca2+-associated signal transduction pathways that increase the activity of protein phosphatases 2A and 2B, which in turn dephosphorylate tau.
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PMID:Apolipoprotein E (ApoE) peptide regulates tau phosphorylation via two different signaling pathways. 951 10