alpha 7 Nicotinic receptor activation reduces beta-amyloid-induced apoptosis by inhibiting caspase-independent death through phosphatidylinositol 3-kinase signaling

作者：Yu Wenfeng; Mechawar Naguib; Krantic Slavica; Quirion Remi^*

来源：Journal of Neurochemistry, 2011, 119(4): 848-858.

DOI：10.1111/j.1471-4159.2011.07466.x

• amyloid-beta
• apoptosis inducing factor
• neuronal culture
• neuroprotection
• nicotine
• phosphatidylinositol 3-kinase

The neurotoxicity of amyloid-beta (A beta) 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 A beta 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 A beta(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 alpha 7nicotinic acetylcholine receptor(nAChR) antagonist (methyllycaconitine), but not the alpha 4 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 alpha 7 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 A beta(1-42)-treated neurons. These findings indicate that the alpha 7 nAChR activation and PI3K/Akt transduction signaling contribute to the neuroprotective effects of nicotine against A beta-induced cell death by modulating caspase-independent death pathways.

• 出版日期2011-11