Estrogen and beta-amyloid toxicity: role of integrin and PI3-K.
Beta-amyloid peptide (betaAP) induces apoptosis and down-regulation of alpha(1)beta(1) integrin in neuronal cells, indicating a relationship between betaAP neurotoxicity and modulation of integrin expression. Estrogen may play a role in protecting women from Alzheimer Disease (AD). It is here reported that both 17beta-estradiol (17betaE(2)) and its non-estrogenic stereoisomer 17alpha-estradiol (17alphaE(2)) rescue neuronal cells from betaAP-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 17betaE(2) protection against betaAP-induced apoptosis. 17betaE(2) up-regulates alpha(1)beta(1) integrin expression and completely abolishes betaAP-induced alpha(1)beta(1) down-regulation. Inadequate cell cycle control may contribute to neuronal death in AD. betaAP induces RA-SK-N-BE cells to enter cell cycle, which remains incomplete. 17betaE(2) induces betaAP-treated cells to complete cell cycle. Our data suggest that estrogen protects from betaAP neurotoxicity by restoring integrin expression and cell cycle control.
Department of Clinical and Experimental Medicine, University of Piemonte Orientale A. Avogadro, Novara, Italy. chiarella.bozzo@med.unipmn.it
Chiarella
C
Bozzo
Francesca
F
Graziola
Annalisa
A
Chiocchetti
Pier Luigi
PL
Canonico
D016229:Amyloid beta-Peptides / Q000009:adverse effects / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D019610:Cytoprotection; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D039222:Integrin alpha1beta1 / Q000032:analysis / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D015854:Up-Regulation / Q000187:drug effects
D016229:Amyloid beta-Peptides; D004958:Estradiol; D039222:Integrin alpha1beta1; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011960:Receptors, Estrogen