alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block a beta-amyloid-induced neurotoxicity

Multiple lines of evidence, from molecular and cellular to epidemiological, have implicated nicotinic transmission in the pathogenesis of Alzheimer's disease (AD). Here we show the signal transduction mechanism involved in ni cotinic receptor-mediated protection against beta -amyloid-enhanced glutama te neurotoxicity. Nicotine-induced protection was suppressed by an alpha7 n icotinic receptor antagonist (alpha -bungarotoxin), a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002 and wortmannin), and a Src inhibitor (P P2). Levels of phosphorylated Akt, an effector of PI3K, and Bcl-2 were incr eased by nicotine. The alpha7 nicotinic receptor was physically associated with the PI3K p85 subunit and Fyn. These findings indicate that the alpha7 nicotinic receptor trans duces signals to PI3K in a cascade, which ultimate ly contributes to a neuroprotective effect. This might form the basis of a new treatment for AD.