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 17Α-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. 17αE₂ 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.