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

Abnormal hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase 3 beta (GSK-3 beta) is a primary tau kinase that is most implicated in tau pathology in AD. However, the exact molecular nature of GSK-3 beta involved in AD is unclear. In the present study, we found that GSK-3 beta was truncated at C-terminus and correlated with over-activation of calpain I in AD brain. Truncation of GSK-3 beta was positively correlated with tau hyperphosphorylation, tangles score and Braak stage in human brain. Calpain I proteolyzed GSK-3 beta 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 beta 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 beta by Ca2+/calpain I markedly increases its activity and involvement of this mechanism probably is responsible for up-regulation of GSK-3 beta and consequent abnormal hyperphosphorylation of tau and neurofibrillary degeneration in AD.