Roles of Nicotinic Acetylcholine Receptors in the Pathology and Treatment of Alzheimer’s and Parkinson’s Diseases

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 those pathogenesis. This review presents evidences of nicotinic acetylcholine receptor (nAChR)-mediated protection against neurotoxicity induced by β amyloid (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-PI3K-AKT pathway and subsequent upregulation of Bcl-2 and Bcl-x, would lead to neuroprotection. Recently analyzing the properties of galantamine, we clarified the 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 Ca influx into microglia. The Ca-induced intracellular signaling cascades may then stimulate Aβ phagocytosis through the actin reorganization. This discovery would facilitate further investigation of possible nAChRs enhancing drugs targeting not only neuronal but also microglial nAChRs.