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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