Nicotinic receptor-mediated protection against beta-amyloid neurotoxicity

Multiple lines of evidence, from molecular and cellular to epidemiologic, h ave implicated nicotinic transmission in the pathology of Alzheimer's disea se. In this review we present evidence for nicotinic receptor-mediated prot ection against beta -amyloid and glutamate neurotoxicity, and the signal tr ansduction involved in this mechanism. The data are based mainly on our stu dies using rat-cultured primary neurons. Nicotine-induced protection was bl ocked by an alpha7 nicotinic receptor antagonist, a phosphatidylinositol 3- kinase inhibitor, and an Src inhibitor. Levels of phosphorylated Akt, an ef fector of phosphatidylinositol 3-kinase; Bcl-2; and Bcl-x were increased by nicotine administration. From these experimental data, our hypothesis for the mechanism of nicotinic receptor-mediated survival signal transduction i s that the alpha7 nicotinic receptor stimulates the Src family, which activ ates phosphatidylinositol 3-kinase to phosphorylate Akt, which subsequently transmits the signal to upregulate Bcl-2 and Bcl-x. Upregulation of Bcl-2 and Bcl-x could prevent cells from neuronal death induced by beta -amyloid and glutamate. These findings suggest that an early diagnosis of Alzheimer' s disease and protective therapy with nicotinic receptor stimulation could delay the progress of Alzheimer's disease. (C) 2001 Society of Biological P sychiatry.