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

β-Amyloid peptide (βAP) induces apoptosis and down-regulation of α1β1 integrin in neuronal cells, indicating a relationship between βAP neurotoxicity and modulation of integrin expression. Estrogen may play a role in protecting women from Alzheimer Disease (AD). It is here reported that both 17β-estradiol (17βE2) and its non-estrogenic stereoisomer 17α-estradiol (17αE2) rescue neuronal cells from βAP-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 17βE2 protection against βAP-induced apoptosis. 17βE2 up-regulates α1β1 integrin expression and completely abolishes βAP-induced α1β1 down-regulation. Inadequate cell cycle control may contribute to neuronal death in AD. βAP induces RA-SK-N-BE cells to enter cell cycle, which remains incomplete. 17βE2 induces βAP-treated cells to complete cell cycle. Our data suggest that estrogen protects from βAP neurotoxicity by restoring integrin expression and cell cycle control.