Truncation and activation of GSK-3? by calpain I: a molecular mechanism links to tau hyperphosphorylation in Alzheimer's disease.

ABSTRACT: Abnormal hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase 3? (GSK-3?) is a primary tau kinase that is most implicated in tau pathology in AD. However, the exact molecular nature of GSK-3? involved in AD is unclear. In the present study, we found that GSK-3? was truncated at C-terminus and correlated with over-activation of calpain I in AD brain. Truncation of GSK-3? was positively correlated with tau hyperphosphorylation, tangles score and Braak stage in human brain. Calpain I proteolyzed GSK-3? in vitro at C-terminus, leading to an increase of its kinase activity, but keeping its characteristic to preferentially phosphorylate the protein kinase A-primed tau. Excitotoxicity induced by kainic acid (KA) caused GSK-3? truncation at C-terminus and hyperphosphorylation of tau in mouse brain. Inhibition of calpain prevented the KA-induced changes. These findings suggest that truncation of GSK-3? by Ca(2+)/calpain I markedly increases its activity and involvement of this mechanism probably is responsible for up-regulation of GSK-3? and consequent abnormal hyperphosphorylation of tau and neurofibrillary degeneration in AD.

SUBMITTER: Jin N 

PROVIDER: S-EPMC4313118 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature