Inhibition of Glycogen Synthase Kinase-3 Reverses Tau Hyperphosphorylation Induced by Pin1 Down-Regulation

Yan-Si      Xiong; Dan-Li      Wang; Lu      Tan; Xiong      Wang; Li-Ming      Chen; Cheng-Xin      Gong; Jian-Zhi      Wang; Ling-Qiang      Zhu

Abstract

One of the neuropathological hallmarks of Alzheimer’s disease (AD) is the occurrence of neurofibrillary tangles (NFTs) that are composed of abnormally hyperphosphorylated microtubule-associated protein tau. Abnormal tau hyperphosphorylation is mainly induced due to the imbalance between protein kinases and phosphatases. In the tanglerich subregions of the hippocampus and parietal cortex in the brain of AD patients, the levels of the phosphorylationdependent protein peptidyl-prolyl cis-trans isomerase (Pin1) were found to be low. Although Pin1 can regulate tau phosphorylation, it is not clear whether the inhibition of glycogen synthase kinase 3 (GSK-3), the primary mediator of tau phosphorylation in AD, could reverse tau hyperphosphorylation induced due to the down-regulation of Pin1. We found that while suppression of Pin1, either by using its inhibitor Juglone or a shRNA plasmid against Pin1, induces tau hyperphosphorylation and GSK-3β activation both in vivo and in vitro, inhibition of GSK-3β by SB216763 or LiCl reverses tau hyperphosphorylation. Our data suggest that GSK-3β activation plays an important role in tau hyperphosphorylation induced by the down-regulation of Pin1, and the inhibition of GSK-3β might be a potential therapeutic approach for AD pathology.

Keywords: Alzheimer’s disease, GSK-3β, phosphorylation, Pin1, SB216763, shRNA, tau.

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