Yu_2011_J.Neurochem_119_848

The neurotoxicity of amyloid-beta (Abeta) involves caspase-dependent and -independent programmed cell death. The latter is mediated by the nuclear translocation of the mitochondrial flavoprotein apoptosis inducing factor (AIF). Nicotine has been shown to decrease Abeta neurotoxicity via inhibition of caspase-dependent apoptosis, but it is unknown if its neuroprotection is mediated through caspase-independent pathways. In the present study, pre-treatment with nicotine in rat cortical neuronal culture markedly reduced Abeta(1-42) induced neuronal death. This effect was accompanied by a significant reduction of mitochondrial AIF release and its subsequent nuclear translocation as well as significant inhibition of cytochrome c release and caspase 3 activation. Pre-treatment with selective alpha7nicotinic acetylcholine receptor(nAChR) antagonist (methyllycaconitine), but not the alpha4 nAChR antagonist (dihydro-beta-erythroidine), could prevent the neuroprotective effect of nicotine on AIF release/translocation, suggesting that nicotine inhibits the caspase-independent death pathway in a alpha7 nAChR-dependent fashion. Furthermore, the neuroprotective action of nicotine on AIF release/translocation was suppressed by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. Pre-treatment with nicotine significantly restored Akt phosphorylation, an effector of PI3K, in Abeta(1-42) -treated neurons. These findings indicate that the alpha7 nAChR activation and PI3K/Akt transduction signaling contribute to the neuroprotective effects of nicotine against Abeta-induced cell death by modulating caspase-independent death pathways.