title: 17beta-estradiol attenuates glycogen synthase kinase-3beta activation and tau hyperphosphorylation in Akt-independent manner.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hai-Rong
authors.initials: HR
authors.lastname: Shi
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
authors.forename: Shao-Hui
authors.initials: SH
authors.lastname: Wang
authors.forename: Xin-An
authors.initials: XA
authors.lastname: Liu
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
mesh_terms: 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*
chemical_list: 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