A novel defense mechanism that is activated on amyloid- β insult to mediate cell survival: role of SGK1-STAT1/STAT2 signaling

Amyloid- β (A β ) is known to induce apoptotic cell death and its underlying mechanism has been studied extensively, but the endogenous protection mechanism that results from A β insult is less known. In this study, we have found that A β 1−42 produced a dose-dependent decrease in cell viability and dose-dependent increase in apoptotic cell death in PC12 cells. Meanwhile, A β 1−42 (0.1 μ M) increased the phosphorylation of serum- and glucocorticoid-inducible kinase1 (SGK1) at Ser-78 specifically. A parallel increase in ERK1/2, STAT1 and STAT2 phosphorylation and the anti-apoptotic gene Mcl-1 expression was also observed. Transfection of rat siRNAs against ERK1/2, SGK1, STAT1 and STAT2 abolished these effects of A β . Transfection of sgkS78D , the constitutively active SGK1, dose-dependently protected against A β -induced apoptosis and dose-dependently increased the expression of Mcl-1. SGK1 activation further phosphorylates STAT1 at Tyr-701 and Ser-727 directly, and activates STAT2 at Tyr-690 indirectly. Phosphorylation of STAT1/STAT2 upregulated Mcl-1 expression which in turn protected against A β -induced apoptosis. But Mcl-1 siRNA transfection enhanced A β -induced apoptosis. Mutation of SGK1 at Ser-78 blocked the effect of A β on STAT1/STAT2 phosphorylation and Mcl-1 expression. Further, mutation of STAT1/STAT2 prevented the effect of both A β and SGK1 on Mcl-1 expression. These results together showed a novel endogenous protection mechanism that is activated on A β insult to mediate cell survival.