17 beta-estradiol attenuates glycogen synthase kinase-3 beta 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-3 beta (GSK-3 beta) is a major tau kinase. However, the role of estrogen on GSK3 beta-induced tau hyperphosphorylation is elusive. Here, we treated N2a cells with wortmannin (Wort) and GF-109203X (GFX) or gene transfection to activate GSK-3 beta and to induce tau hyperphosphorylation and then the effects of 17 beta-estradiol (beta E2) on tau phosphorylation and GSK-3 beta activity were studied. We found that beta E2 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-3 beta. Simultaneously, it increased the level of Ser9-phosphorylated (inactive) GSK-3 beta. To study whether the protective effect of beta E2 on GSK-3 beta 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 beta E2 could attenuate Wort/GFX-induced GSK-3 beta activation and tau hyperphosphorylation with Akt-independent manner. It suggests that beta E2 may arrest AD-like tau hyperphosphorylation by directly targeting GSK-3 beta.