Phosphorylation of tau antagonizes apoptosis by stabilizing β-catenin, a mechanism involved in Alzheimer's nerodegeneration

Hong Lian Li, Hai Hong Wang, Shi Jie Liu, Yan Qiu Deng, Yong Jie Zhang, Qing Tian, Xiao Chuan Wang, Xiao Qian Chen, Ying Yang, Jia Yu Zhang, Qun Wang, Huaxi Xu, Francesca Fang Liao, Jian Zhi Wang

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197 Citations (Scopus)

Abstract

Hyperphosphorylated tau is the major protein subunit of neurofibrillary tangles in Alzheimer's disease (AD) and related tauopathies. It is not understood, however, why the neurofibrillary tangle-containing neurons seen in the AD brains do not die of apoptosis but rather degeneration even though they are constantly awash in a proapoptotic environment. Here, we show that cells overexpressing tau exhibit marked resistance to apoptosis induced by various apoptotic stimuli, which also causes correlated tau hyperphosphorylation and glycogen synthase kinase 3 (GSK-3) activation. GSK-3 overexpression did not potentiate apoptotic stimulus-induced cell apoptosis in the presence of high levels of tau. The resistance of neuronal cells bearing hyperphosphorylated tau to apoptosis was also evident by the inverse staining pattern of PHF-1-positive tau and activated caspase-3 or fragmented nuclei in cells and the brains of rats or tau-transgenic mice. Tau hyperphosphorylation was accompanied by decreases in β-catenin phosphorylation and increases in nuclear translocation of β-catenin. Reduced levels of β-catenin antagonized the antiapoptotic effect of tau, whereas overexpressing β-catenin conferred resistance to apoptosis. These results reveal an antiapoptotic function of tau hyperphosphorylation, which likely inhibits competitively phosphorylation of β-catenin by GSK-3β and hence facilitates the function of β-catenin. Our findings suggest that tau phosphorylation may lead the neurons to escape from an acute apoptotic death, implying the essence of neurodegeneration seen in the AD brains and related tauopathies.

Original languageEnglish
Pages (from-to)3591-3596
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number9
DOIs
Publication statusPublished - 27 Feb 2007
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Glycogen synthase kinase-3
  • Tau hyperphosphorylation

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