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.
Bozzo
Chiarella
C
Department of Clinical and Experimental Medicine, University of Piemonte Orientale A. Avogadro, Novara, Italy. chiarella.bozzo@med.unipmn.it
Graziola
Francesca
F
Chiocchetti
Annalisa
A
Canonico
Pier Luigi
PL
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