A Novel Nicotinic Mechanism Underlies Î²-Amyloid-Induced Neurotoxicity
Abstract Loss of basal forebrain cholinergic neurons (BFCN) correlates with cognitive deficits in Alzheimer disease (AD). Our recent evidence suggests that chronic exposure to AÎ² up-regulated neuronal Î±7-nAChRs and increased neuronal excitability in cultured hippocampal neurons. However, the impact of the up-regulated Î±7-nAChRs on AÎ²-induced neurotoxicity remains unclear. In this study, we investigated the role of Î±7-nAChRs in the mediation of AÎ²-induced neurotoxicity. The effects of AÎ² exposure on Î±7-nAChRs and cytotoxicity were examined using whole-cell patch clamp recordings, atomic force microscope (AFM) imaging, immunoprecipitation, and lactate dehydrogenase (LDH) release assay in primary cultured hippocampal neurons as well as differentiated human neuroblastoma (SH-SY5Y) cells with cholinergic characteristics. We found that Î±7-nAChRs are necessary for AÎ²-induced neurotoxicity in hippocampal neurons because chronic AÎ² significantly increased LDH level in hippocampal cultures, which was prevented by either Î±7-nAChR antagonist methyllycaconitine (MLA) or by Î±7 subunit gene deletion (cultures prepared from nAChR Î±7 subunit KO mice), whereas Î²2-containing nAChR antagonist (dihydro-Î²-erythroidine, DhÎ²E) or the genetic deletion of nAChR Î²2 subunit (cultures prepared from Î²2 KO mice) failed to prevent AÎ²-induced toxicity. In SH-SY5Y cells, larger aggregates of AÎ² preferentially up-regulated Î±7-nAChR expression and function accompanied by a significant decrease in cell viability. Co-treatment MLA, but not mecamylamine (MEC), prevented AÎ² exposure-induced neurotoxicity. Our results suggest a detrimental role of upregulated Î±7-nAChRs in the mediation of AÎ²-induced neurotoxicity.
Digital Object Identifier (DOI)
Liu, Qiang; Xie, Xitao; Emadi, Sharareh; Sierks, Michael R.; and Wu, Jie, "A Novel Nicotinic Mechanism Underlies Î²-Amyloid-Induced Neurotoxicity" (2015). Translational Neuroscience. 401.