Truncation and activation of GSK-3β 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 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.

Glucocorticoid receptors signaling impairment potentiates amyloid‐β oligomers‐induced pathology in an acute model of Alzheimer’s disease

“…Indeed, GR can be phosphorylated on several serine and threonine residues. 53 Calpain 1 is particularly involved in the activation of GSK-3β, 54 and in the maturation of p35 in p25 55 ( Figure 4A,F). 49,50 We first confirmed changed expression ratios of p(Ser9)GSK-3β/ GSK-3β and p(Tyr216)GSK-3β/GSK-3β 51 ( Figure 4A-C), reflecting an increase in GSK-3β activation.…”

Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia

“…For example, D’Orsi and colleagues showed that calpain activation occurs downstream of mitochondrial engagement during excitotoxic apoptosis [55]. Additionally, in Alzheimer’s disease µ-calpain activates GSK-3β [56]. Because EPO signaling modulates kinase activity, including activating Akt and inhibiting GSK-3β [57], EPO may be impacting calpain activity by altering the balance of Akt/GSK-3β activation.…”

Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration

“…Whether Cdk5/p25 is responsible for tau hyperphosphorylation under pathological conditions, including in Alzheimer’s disease (AD) or frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), is still controversial; further studies are needed to provide a convincing link between calpain activation, Cdk5 hyperactivation and tau hyperphosphorylation [62]. Another link between calpain, tau hyperphosphorylation and AD is provided by calpain-mediated truncation of GSK-3β [67–69]. Calpain truncates GSK-3β in its C-terminal domain, resulting in increased kinase activity; in human AD brain, GSK-3β truncation is correlated with tau hyperphosphorylation, tangle score and Braak stage [69].…”

“…Another link between calpain, tau hyperphosphorylation and AD is provided by calpain-mediated truncation of GSK-3β [67–69]. Calpain truncates GSK-3β in its C-terminal domain, resulting in increased kinase activity; in human AD brain, GSK-3β truncation is correlated with tau hyperphosphorylation, tangle score and Braak stage [69]. However, increasing Ser9 phosphorylation by inhibiting certain phosphatases, such as phosphatase 1/2A prevented calpain-mediated cleavage of GSK-3β [68], indicating that the relationship between calpain, GSK-3β and tau hyperphosphorylation is extremely complex.…”