Tau overexpression inhibits cell apoptosis with the mechanisms involving multiple viability-related factors.
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 beta-catenin were also detected in N2a/tau cells, and knockdown of beta-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 beta-catenin and p53-mitochondria-caspase-mediated apoptotic pathways.
Wang
Hai-Hong
HH
Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Li
Hong-Lian
HL
Liu
Rong
R
Zhang
Yao
Y
Liao
Kai
K
Wang
Qun
Q
Wang
Jian-Zhi
JZ
Liu
Shi-Jie
SJ
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002166:Camptothecin / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000009:adverse effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008453:Maytansine / Q000031:analogs & derivatives / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D019311:Staurosporine / Q000009:adverse effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D017304:Annexin A5; D004791:Enzyme Inhibitors; C054369:MAPT protein, human; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C485184:enhanced green fluorescent protein; D016875:tau Proteins; D008453:Maytansine; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D019311:Staurosporine; D002166:Camptothecin