Tau overexpression inhibits cell apoptosis with the mechanisms involving multiple viability-related factors

Hai Hong Wang, Hong Lian Li, Rong Liu, Yao Zhang, Kai Liao, Qun Wang, Jian Zhi Wang, Shi Jie Liu

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28 Citations (Scopus)

Abstract

The formation of neurofibrillary tangles, mainly composed of hyperphosphorylated tau protein, is a hallmark in the brain of human tauopathies, including Alzheimer's disease (AD). Although neurons bearing neurofibrillary tangles are constantly exposed to various apoptotic stimuli, they do not appear to preferentially die by apoptosis. The underlying mechanism for such resistance to apoptosis remains elusive. Previously, we studied the role of tau phosphorylation in apoptosis and found that tau hyperphosphorylation by glycogen synthase kinase-3 (GSK-3) rendered cells more resistant to apoptosis. In this study, we show that the overexpression of tau without any exogenous activation of kinases also confers increased resistance to apoptosis in both N2a cells and in a tau transgenic mouse model. Mechanistically, the overexpression of tau was associated with a reduced p53 level, decreased release of cytochrome C from mitochondria, and inhibition of caspases-9/-3. Additionally, a decreased phosphorylation and increased nuclear translocation of β-catenin were also detected in N2a/tau cells, and knockdown of β-catenin eliminated the anti-apoptotic effect of tau. Furthermore, tau was spontaneously hyperphosphorylated upon overexpression and by staurosporine treatment. The phosphorylation level of p53 decreased upon tau overexpression, and a more profound reduction of the phosphorylated p53 was detected when the cells were treated with lithium and roscovitine, inhibitors of GSK-3 and cyclin-dependent kinase-5 (Cdk-5). These results suggest that the overexpression of tau, which may be hyperphosphorylated by endogenous GSK-3 and Cdk-5, is anti-apoptotic by mechanisms involving modulation of multiple anti-apoptotic factors, including β-catenin and p53-mitochondria-caspase-mediated apoptotic pathways.

Original languageEnglish
Pages (from-to)167-179
Number of pages13
JournalJournal of Alzheimer's Disease
Volume21
Issue number1
DOIs
Publication statusPublished - 1 Jan 2010
Externally publishedYes

Keywords

  • Alzheimer's disease
  • apoptosis
  • GSK-3
  • tau
  • β-catenin

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