| First Author | Ma SL | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 10 | Pages | 6969-73 |
| PubMed ID | 22184106 | Mgi Jnum | J:182777 |
| Mgi Id | MGI:5316567 | Doi | 10.1074/jbc.C111.298596 |
| Citation | Ma SL, et al. (2012) Prolyl isomerase Pin1 promotes amyloid precursor protein (APP) turnover by inhibiting glycogen synthase kinase-3beta (GSK3beta) activity: novel mechanism for Pin1 to protect against Alzheimer disease. J Biol Chem 287(10):6969-73 |
| abstractText | Alzheimer disease (AD) is characterized by the presence of senile plaques of amyloid-beta (Abeta) 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-3beta (GSK3beta) 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 GSK3beta to inhibit its kinase activity. Furthermore, Pin1 promotes protein turnover of APP by inhibiting GSK3beta activity. A point mutation either at Thr-330, the Pin1-binding site in GSK3beta, or at Thr-668, the GSK3beta phosphorylation site in APP, abolished the regulation of GSK3beta 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 GSK3beta kinase activity to reduce APP protein levels, providing a previously unrecognized mechanism by which Pin1 protects against Alzheimer disease. |
