Nicotinic receptor-mediated protection against beta-amyloid neurotoxicity.
Multiple lines of evidence, from molecular and cellular to epidemiologic, have implicated nicotinic transmission in the pathology of Alzheimer's disease. In this review we present evidence for nicotinic receptor-mediated protection against beta-amyloid and glutamate neurotoxicity, and the signal transduction involved in this mechanism. The data are based mainly on our studies using rat-cultured primary neurons. Nicotine-induced protection was blocked by an alpha7 nicotinic receptor antagonist, a phosphatidylinositol 3-kinase inhibitor, and an Src inhibitor. Levels of phosphorylated Akt, an effector 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 is that the alpha7 nicotinic receptor stimulates the Src family, which activates 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.
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Shimohama
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Kihara
D000544:Alzheimer Disease / Q000503:physiopathology / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D006801:Humans; D009538:Nicotine / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology
D016229:Amyloid beta-Peptides; D011978:Receptors, Nicotinic; D009538:Nicotine