title: Stimulating nicotinic receptors trigger multiple pathways attenuating cytotoxicity in models of Alzheimer's and Parkinson's diseases.
abstract: Both of the two most common neurodegenerative disorders, namely Alzheimer's disease (AD) and Parkinson's disease (PD), have multiple lines of evidence from molecular and cellular to epidemiological, that nicotinic transmission is implicated in their pathogenesis. This review article presents evidence of nicotinic acetylcholine receptor (nAChR)-mediated protection against neurotoxicity induced by amyloid-β (Aβ), glutamate, rotenone, and 6-hydroxydopamine (6-OHDA) and the signal transduction involved in this mechanism. Our studies clarified that survival signal transduction, α7 nAChR-Src family-PI3 K-AKT pathway, and subsequent upregulation of Bcl-2 and Bcl-x, would lead to neuroprotection. In addition to the PI3 K-AKT pathway, two other survival pathways, JAK2/STAT3 and MEK/ERK, are proposed by other groups. These three survival pathways are related to each other through intracellular signal transductions in neurons. The JAK2/STAT3 pathway is cholinergic anti-inflammation pathway mediated by α7 nAChR on macrophage and microglia as well as neuron. Recently analyzing the properties of galantamine, we clarify the 4th independent neuroprotective pathway, which is mediated by enhancement of microglial α7 nAChR resulting in upregulation of Aβ phagocytosis. Galantamine sensitizes microglial α7 nAChRs to choline and induce Ca2+ influx into microglia. The Ca2+-induced intracellular signaling cascades may then stimulate Aβ phagocytosis through actin reorganization. The discovery of the 4th pathway would facilitate further investigation of possible nAChRs enhancing drugs targeting not only neuronal but also microglial nAChRs.
authors.affiliation: Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kawamata
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D018678:Cholinergic Agents / Q000494:pharmacology; D006801:Humans; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009498:Neurotoxins / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D018678:Cholinergic Agents; D009498:Neurotoxins; D011978:Receptors, Nicotinic