Abstract
Early intracellular events responsible for cell‐cycle induction by β‐amyloid (Aβ) in neurons have not been identified yet. Extracellular signal–regulated kinases 1/2 (ERK1/2) have been identified in this pathway, and inhibition of ERK activity prevents cell‐cycle activation and reduces neuronal death induced by Aβ. To identify upstream events responsible for ERK activation, attention has been focused on integrins. Treatment of SH‐SY5Y cells, differentiated by long‐term exposure to 10 μM retinoic acid with a neutralizing anti‐α1‐integrin antibody significantly reduced Aβ‐induced neuronal death. However, cell‐cycle analysis showed that treatment with anti‐α1‐integrin per se produced changes in the distribution of cell populations, thus hampering any effect on Aβ‐induced cell‐cycle activation. 4‐Amino‐5‐(4‐chlorophenyl)‐7(t‐butyl)pyrazol(3,4‐D)pyramide, an inhibitor of src protein kinases that colocalizes with focal adhesion kinase (FAK) and is involved in integrin signaling, was effective in reducing activation of the cell cycle and preventing induction of neuronal death by Aβ while inhibiting ERK1/2 phosphorylation. Similar results were obtained when FAK expression was down‐regulated by siRNA silencing. The present study identifies a sequence of early events in the toxic effect of Aβ in neuronal cultures that involves interaction with integrins, activation of FAK/src, enhanced phosphorylation of ERK1/2, and induction of the cell cycle, all leading to neuronal death. © 2007 Wiley‐Liss, Inc.