title: Pretreatment of PC12 cells with 17β-estradiol prevents Aβ-induced down-regulation of CREB phosphorylation and prolongs inhibition of GSK-3β.
abstract: It is believed that estrogen protects neurons against various toxicities like that from amyloid β (Aβ) in Alzheimer's disease (AD). In the present study, we investigated the effects of Aβ1-42 on the activities of cyclic-AMP response element-binding protein (CREB) and glycogen synthase kinase-3β (GSK-3β), two key proteins associated with learning and memory, and the effects of 17β-estradiol on Aβ(1-42)-induced changes of CREB and GSK-3β in PC12 cells. We found that Aβ1-42 induced a decrease in phosphorylation of CREB at Ser133 (CREB pS133) and caused a transient (30 min) up-regulation of the inhibitory GSK-3β phosphorylation at Ser9 (GSK-3β pS9), followed by down-regulation of GSK-3β pS9. Pretreatment of 17β-estradiol is needed for its protection against Aβ1-42-induced changes of CREB. The protective role of 17β-estradiol against Aβ(1-42)-induced down-regulation of CREB pS133 was abolished by the mitogen-activated protein kinase (MAPK) pathway inhibitor U0126. Furthermore, 17β-estradiol also prolonged the up-regulation of GSK-3β pS9 for at least 8 h. However, this action of 17β-estradiol was abrogated by PKA inhibitor H-89, AKT inhibitor LY294002, and MAPK inhibitor U0126. These results suggest that, while the protection of 17β-estradiol on CREB is MAPK dependent, its effect on GSK-3β integrates several pathways. These studies provide new insights into the role of estrogen in memory and AD.
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei, China.
authors.forename: Yanxing
authors.initials: Y
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Run
authors.forename: Zhou
authors.initials: Z
authors.lastname: Sun
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Shenggang
authors.initials: S
authors.lastname: Sun
authors.forename: Zhihou
authors.initials: Z
authors.lastname: Liang
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015536:Down-Regulation; D004958:Estradiol / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D017362:Cyclic AMP Response Element-Binding Protein; D047428:Protein Kinase Inhibitors; D004958:Estradiol; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3