Pretreatment of PC12 cells with 17ß-estradiol prevents Aß-induced down-regulation of CREB phosphorylation and prolongs inhibition of GSK-3ß.

Journal of molecular neuroscience : MN

PubMedID: 23266915

Chen Y, Su Y, Run X, Sun Z, Wang T, Sun S, Liang Z. Pretreatment of PC12 cells with 17ß-estradiol prevents Aß-induced down-regulation of CREB phosphorylation and prolongs inhibition of GSK-3ß. J Mol Neurosci. 2013;50(3):394-401.
It is believed that estrogen protects neurons against various toxicities like that from amyloid ß (Aß) in Alzheimer's disease (AD). In the present study, we investigated the effects of Aß1-42 on the activities of cyclic-AMP response element-binding protein (CREB) and glycogen synthase kinase-3ß (GSK-3ß), two key proteins associated with learning and memory, and the effects of 17ß-estradiol on Aß(1-42)-induced changes of CREB and GSK-3ß in PC12 cells. We found that Aß1-42 induced a decrease in phosphorylation of CREB at Ser133 (CREB pS133) and caused a transient (30 min) up-regulation of the inhibitory GSK-3ß phosphorylation at Ser9 (GSK-3ß pS9), followed by down-regulation of GSK-3ß pS9. Pretreatment of 17ß-estradiol is needed for its protection against Aß1-42-induced changes of CREB. The protective role of 17ß-estradiol against Aß(1-42)-induced down-regulation of CREB pS133 was abolished by the mitogen-activated protein kinase (MAPK) pathway inhibitor U0126. Furthermore, 17ß-estradiol also prolonged the up-regulation of GSK-3ß pS9 for at least 8 h. However, this action of 17ß-estradiol was abrogated by PKA inhibitor H-89, AKT inhibitor LY294002, and MAPK inhibitor U0126. These results suggest that, while the protection of 17ß-estradiol on CREB is MAPK dependent, its effect on GSK-3ß integrates several pathways. These studies provide new insights into the role of estrogen in memory and AD.