O1‐07‐06: Truncation of GSK‐3beta by calpain I contributes to the hyperphosphorylation of tau in the Alzheimer's brain
Year: 2012
Type: article
Abstract: Microtubule-associated protein tau is abnormally hyperphosphorylated and deposited as neurofibrillary tangles (NFTs) in neurons in Alzheimer disease (AD) brain and related tauopathies. The altered tau is believed to be pivotal to the pathogenesis of AD, but the molecular mechanism leading to the abnormal hyperphosphorylation of this protein is not fully understood. GSK-3b is a major tau kinase and phosphorylates tau at many sites that are phosphorylated in AD brain, suggesting that GSK-3b plays a critical role in the regulation of tau phosphorylation and neurofibrillary pathology in AD. To date, direct evidence of GSK-3b upregulation in AD brain has not been reported. The protein levels of GSK-3b, calpain I and tau phosphorylation were determined by Western blots and immuno-dot blots. The cleavage and the cleavage site(s) of GSK-3b by calpain I were determined by in vitro proteolysis and Western blots. The GSK-3b activity of the proteolyzed or unproteolyzed enzyme was measured by using recombinant human tau441 as a substrate. The relationship between calpain I over-activation and GSK-3b truncation or tau phosphorylation was analyzed by the Pearson correlation. We found that in AD brain, GSK-3β was truncated into 41 kDa from 46 kDa. The truncation of GSK-3b was positively correlated to the truncation and activation of calpain I in human brains. Truncated GSK-3b reacted with GSK-3b antibodies against N-terminus, but not C-terminus, indicating that the truncation of GSK-3b in AD is at its C-terminus. Calpain I cleaved GSK-3b at the C-terminus to generate a 41-kDa truncated form in vitro, and the truncation increased its kinase activity toward tau441 markedly. Like unproteolyzed GSK-3b, proteolyzed GSK-3b phosphorylated tau site-specifically. Pre-phosphorylation of tau by PKA primed tau to be a better substrate for the truncated GSK-3b, suggesting that the proteolysis did not change the priming characteristic of GSK-3b. Truncation of GSK-3b was positively correlated to tau phosphorylation in human brains. These data suggest that calpain I cleaves GSK-3b at the C-terminus and enhances its kinase activity toward tau. Overactivation of calpain I due to overload of intraneuronal calcium in AD may cleave GSK-3b and up-regulates its activity, leading to tau hyperphosphorylation and neurofibrillary degeneration.
Source: Alzheimer s & Dementia
Institution: Nantong University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2113417002