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- W2036765013 abstract "Abnormally hyperphosphorylated τ is the major protein component of neurofibrillary tangles, the characteristic lesion of Alzheimer's disease (AD). Protein phosphatases (PP) type 1 (PP-1), type 2A (PP-2A) and type 2B (PP-2B) appear to be involved in the regulation of τ phosphorylation. The incidence of neurofibrillary tangles is higher in brains of schizophrenic patients treated with neuroleptics than in those without this treatment. We have found that the commonly used neuroleptics chlorpromazine, trifluoperazine and clozapine inhibit PP-2B but not PP-1 or PP-2A activity towards [32P]phosphorylase kinase as a substrate. When AD abnormally hyperphosphorylated τ is used as a substrate, PP-2B activity is inhibited by trifluoperazine > chlorpromazine > clozapine. Using phosphorylation-dependent monoclonal antibodies, τ−1, AT8 and PHF-1, we have found that the dephosphorylation of the abnormal τ by PP-2B is inhibited at all the sites recognized by these antibodies. The IC50 of the inhibition of dephosphorylation at τ−1 site is ∼ 20 μM for trifluoperazine and ∼ 120 μM for chlorpromazine. These two neuroleptics inhibit τ dephosphorylation by PP-2B through antagonizing calmodulin as well as directly interacting with PP-2B. The inhibition of the dephosphorylation of abnormally hyperphosphorylated τ by neuroleptics raises an intriguing possibility that the chronic use of these drugs might contribute to neurofibrillary degeneration in schizophrenic and AD patients." @default.
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- W2036765013 date "1996-11-01" @default.
- W2036765013 modified "2023-10-14" @default.
- W2036765013 title "Inhibition of protein phosphatase-2B (calcineurin) activity towards Alzheimer abnormally phosphorylated τ by neuroleptics" @default.
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- W2036765013 doi "https://doi.org/10.1016/s0006-8993(96)00904-3" @default.
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