Estrogen and β-amyloid toxicity: Role of integrin and PI3-K

beta-Amyloid peptide (beta AP) induces apoptosis and down-regulation of alpha(1)beta(1) integrin in neuronal cells, indicating a relationship between beta AP neurotoxicity and modulation of integrin expression. Estrogen may play a role in protecting women from Alzheimer Disease (AD). It is here reported that both 17 beta-estradiol (17 beta E-2) and its non-estrogenic stereoisomer 17 alpha-estradiol (17 alpha E-2) rescue neuronal cells from beta AP-induced apoptosis. As cellular model, the human neuroblastoma cell line SK-N-BE was used, which responds to retinoic acid by growth arrest and differentiation toward the neuronal phenotype (RA-SK-N-BE). Estrogen receptor antagonist does not hinder estrogen protection. Inhibition of phosphatidylinositol 3-kinase (PI3-K), but not of tyrosine kinases or mitogen-activated protein kinases (MAPK) blocks 17 beta E-2 protection against beta AP-induced apoptosis. 17 beta E-2 up-regulates alpha(1)beta(1) integrin expression and completely abolishes beta AP-induced alpha(1)beta(1) down-regulation. Inadequate cell cycle control may contribute to neuronal death in AD. beta AP induces RA-SK-N-BE cells to enter cell cycle, which remains incomplete. 17 beta E-2 induces beta AP-treated cells to complete cell cycle. Our data suggest that estrogen protects from beta AP neurotoxicity by restoring integrin expression and cell cycle control. (C) 2010 Elsevier Inc. All rights reserved.