17beta-estradiol attenuates glycogen synthase kinase-3beta activation and tau hyperphosphorylation in Akt-independent manner.
Decline of estrogen is associated with high incidence of Alzheimer's disease (AD) characterized pathologically with tau hyperphosphorylation, and glycogen synthase kinase-3beta (GSK-3beta) is a major tau kinase. However, the role of estrogen on GSK3beta-induced tau hyperphosphorylation is elusive. Here, we treated N2a cells with wortmannin (Wort) and GF-109203X (GFX) or gene transfection to activate GSK-3beta and to induce tau hyperphosphorylation and then the effects of 17beta-estradiol (betaE2) on tau phosphorylation and GSK-3beta activity were studied. We found that betaE2 could attenuate tau hyperphosphorylation at multiple AD-related sites, including Ser396/404, Thr231, Thr205, and Ser199/202, induced by Wort/GFX or transient overexpression of GSK-3beta. Simultaneously, it increased the level of Ser9-phosphorylated (inactive) GSK-3beta. To study whether the protective effect of betaE2 on GSK-3beta and tau phosphorylation involves protein kinase B (Akt), an upstream effector of GSK-3, we transiently expressed the dominant negative Akt (dnAkt) in the cells. We found that betaE2 could attenuate Wort/GFX-induced GSK-3beta activation and tau hyperphosphorylation with Akt-independent manner. It suggests that betaE2 may arrest AD-like tau hyperphosphorylation by directly targeting GSK-3beta.
Shi
Hai-Rong
HR
Department of Pathophysiology, Key Laboratory of Neurological Disease of Ministry of Education and Hubei Province, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, PR China.
Zhu
Ling-Qiang
LQ
Wang
Shao-Hui
SH
Liu
Xin-An
XA
Tian
Qing
Q
Zhang
Qi
Q
Wang
Qun
Q
Wang
Jian-Zhi
JZ
D000544:Alzheimer Disease / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000077191:Wortmannin; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism*
D000730:Androstadienes; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D018696:Neuroprotective Agents; D016875:tau Proteins; D004958:Estradiol; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C070515:bisindolylmaleimide I; D000077191:Wortmannin