title: α7 Nicotinic receptor activation reduces β-amyloid-induced apoptosis by inhibiting caspase-independent death through phosphatidylinositol 3-kinase signaling.
abstract: The neurotoxicity of amyloid-β (Aβ) 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 Aβ 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 Aβ(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 α7nicotinic acetylcholine receptor(nAChR) antagonist (methyllycaconitine), but not the α4 nAChR antagonist (dihydro-β-erythroidine), could prevent the neuroprotective effect of nicotine on AIF release/translocation, suggesting that nicotine inhibits the caspase-independent death pathway in a α7 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 Aβ(1-42) -treated neurons. These findings indicate that the α7 nAChR activation and PI3K/Akt transduction signaling contribute to the neuroprotective effects of nicotine against Aβ-induced cell death by modulating caspase-independent death pathways.
authors: Douglas Mental Health University Institute, Departments of Psychiatry and Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.
authors: Wenfeng
authors: W
authors: Yu
authors: Naguib
authors: N
authors: Mechawar
authors: Slavica
authors: S
authors: Krantic
authors: Rémi
authors: R
authors: Quirion
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001593:Benzyl Compounds / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018678:Cholinergic Agents / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D018613:Microscopy, Confocal / Q000379:methods; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D016229:Amyloid beta-Peptides; D051033:Apoptosis Inducing Factor; D001593:Benzyl Compounds; C476029:Boc-D-FMK; D018678:Cholinergic Agents; C579165:Chrna7 protein, rat; D004791:Enzyme Inhibitors; D006845:Hydrocarbons, Fluorinated; D009842:Oligopeptides; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D009538:Nicotine; D045304:Cytochromes c; D058539:Phosphatidylinositol 3-Kinase; D020169:Caspases