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[摘要]：Alzheimer disease (AD) is characterized by the presence of senile plaques of amyloid-beta (A beta) peptides derived from amyloid precursor protein (APP) and neurofibrillary tangles made of hyperphosphorylated Tau. Increasing APP gene dosage or expression has been shown to cause familial early-onset AD. However, whether and how protein stability of APP is regulated is unclear. The prolyl isomerase Pin1 and glycogen synthase kinase-3 beta (GSK3 beta) have been shown to have the opposite effects on APP processing and Tau hyperphosphorylation, relevant to the pathogenesis of AD. However, nothing is known about their relationship. In this study, we found that Pin1 binds to the pT330-P motif in GSK3 beta to inhibit its kinase activity. Furthermore, Pin1 promotes protein turnover of APP by inhibiting GSK3 beta activity. A point mutation either at Thr-330, the Pin1-binding site in GSK3 beta, or at Thr-668, the GSK3 beta phosphorylation site in APP, abolished the regulation of GSK3 beta activity, Thr-668 phosphorylation, and APP stability by Pin1, resulting in reduced non-amyloidogenic APP processing and increased APP levels. These results uncover a novel role of Pin1 in inhibiting GSK3 beta kinase activity to reduce APP protein levels, providing a previously unrecognized mechanism by which Pin1 protects against Alzheimer disease. |
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