Abstract
Abnormal hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase 3β (GSK-3β) is a primary tau kinase that is most implicated in tau pathology in AD. However, the exact molecular nature of GSK-3β involved in AD is unclear. In the present study, we found that GSK-3β was truncated at C-terminus and correlated with over-activation of calpain I in AD brain. Truncation of GSK-3β was positively correlated with tau hyperphosphorylation, tangles score and Braak stage in human brain. Calpain I proteolyzed GSK-3β 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-3β 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-3β by Ca2+/calpain I markedly increases its activity and involvement of this mechanism probably is responsible for up-regulation of GSK-3β and consequent abnormal hyperphosphorylation of tau and neurofibrillary degeneration in AD.
Highlights
Truncation and activation of Glycogen synthase kinase 3b (GSK-3b) by calpain I: a molecular mechanism links to tau hyperphosphorylation in Alzheimer’s disease
To understand the role of GSK-3b in tau pathogenesis in Alzheimer’s disease (AD), we determined the expression of GSK-3b in frontal cortices from 7 AD and 7 age- and postmortem interval–matched control brains that were obtained #3.5 h after death (Table S1) by Western blots developed with R127, an antibody against residues 364–377 of GSK-3b
To learn whether the truncation of GSK-3b is resulted from postmortem delay, we first analyzed the difference in postmortem interval (PMI) between AD and Control cases and the relationship of PMI with its truncation
Summary
Truncation and activation of GSK-3b by calpain I: a molecular mechanism links to tau hyperphosphorylation in Alzheimer’s disease. We found that GSK-3b was truncated at C-terminus and correlated with over-activation of calpain I in AD brain. Inhibition of calpain prevented the KA-induced changes These findings suggest that truncation of GSK-3b by Ca21/calpain I markedly increases its activity and involvement of this mechanism probably is responsible for up-regulation of GSK-3b and consequent abnormal hyperphosphorylation of tau and neurofibrillary degeneration in AD. Microtubule-associated protein (MAP) tau is abnormally hyperphosphorylated and aggregated into paired helical filaments (PHFs) or straight filaments (SFs) forming neurofibrillary tangles (NFTs) in the brains of patients with Alzheimer’s disease (AD) and related tauopathies[1,2]. Altered brain calcium homeostasis as well as truncation and activation of calpain I has been reported in AD brain[20,21,22,23]
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