Overexpression of tau proteins antagonizes amyloid-beta-potentiated apoptosis through mitochondria-caspase-3 pathway in N2a cells.
It has been a puzzle why the tangle-bearing neurons in Alzheimer's disease (AD) brain do not die preferentially of apoptosis even though they are actually challenged by multiple proapoptotic factors. Recently, we have reported that phosphorylation of tau can antagonize apoptosis induced by exogenous apoptotic inducers. Amyloid-beta (Abeta), a recognized endogenous proapoptotic factor, is significantly increased in the AD brains, however, it is not known whether tau could abate the Abeta-potentiated apoptosis. Here, we observed that the cells bearing high level of Abeta were more vulnerable than the controls to H2O2-induced apoptosis, and this effect of Abeta was associated with decrease of Bcl-2, elevation of Bax and cytosolic cytochrome-c, as well as activation of caspase-3, suggesting that Abeta could potentiate the oxidant-induced cell apoptosis with involvement of mitochondria-caspase-3 pathway. More importantly, we also found that expression of tau that became hyperphosphorylated could reduce the Abeta-potentiated apoptosis with simultaneous preservation of Bcl-2 and suppression of Bax, cytosolic cytochrome-c, and caspase-3 activity, implying that overexpression of tau that became hyperphosphorylated can attenuate the Abeta-potentiated cell apoptosis through mitochondria-caspase-3 pathway. These findings provide an explanation of the chronic nature of neurodegeneration of neurons with neurofibrillary pathology of abnormal hyperphosphorylated tau in AD and related tauopathies.
Wang
Ze-Fen
ZF
Department of Pathophysiology, Key Laboratory of Neurological Diseases of Educational Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yin
Jun
J
Zhang
Yao
Y
Zhu
Ling-Qiang
LQ
Tian
Qing
Q
Wang
Xiao-Chuan
XC
Li
Hong-Lian
HL
Wang
Jian-Zhi
JZ
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection / Q000379:methods; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C485184:enhanced green fluorescent protein; D016875:tau Proteins; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D053148:Caspase 3