Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer's neurodegeneration.
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 beta-catenin phosphorylation and increases in nuclear translocation of beta-catenin. Reduced levels of beta-catenin antagonized the antiapoptotic effect of tau, whereas overexpressing beta-catenin conferred resistance to apoptosis. These results reveal an antiapoptotic function of tau hyperphosphorylation, which likely inhibits competitively phosphorylation of beta-catenin by GSK-3beta and hence facilitates the function of beta-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.
Li
Hong-Lian
HL
Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Wang
Hai-Hong
HH
Liu
Shi-Jie
SJ
Deng
Yan-Qiu
YQ
Zhang
Yong-Jie
YJ
Tian
Qing
Q
Wang
Xiao-Chuan
XC
Chen
Xiao-Qian
XQ
Yang
Ying
Y
Zhang
Jia-Yu
JY
Wang
Qun
Q
Xu
Huaxi
H
Liao
Francesca-Fang
FF
Wang
Jian-Zhi
JZ
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D051176:beta Catenin / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D051176:beta Catenin; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3