A novel nicotinic mechanism underlies β-amyloid-induced neurotoxicity

Loss of basal forebrain cholinergic neurons (BFCN) correlates with cognitive deficits in Alzheimer disease (AD). Our recent evidence suggests that chronic exposure to A beta up-regulated neuronal alpha 7-nAChRs and increased neuronal excitability in cultured hippocampal neurons. However, the impact of the upregulated alpha 7-nAChRs on A beta-induced neurotoxicity remains unclear. In this study, we investigated the role of alpha 7-nAChRs in the mediation of A beta-induced neurotoxicity. The effects of A beta exposure on alpha 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 alpha 7-nAChRs are necessary for A beta-induced neurotoxicity in hippocampal neurons because chronic A beta significantly increased LDH level in hippocampal cultures, which was prevented by either alpha 7-nAChR antagonist methyllycaconitine (MLA) or by alpha 7 subunit gene deletion (cultures prepared from nAChR alpha 7 subunit KO mice), whereas beta 2-containing nAChR antagonist (dihydro-beta-erythroidine, Dh beta E) or the genetic deletion of nAChR beta 2 subunit (cultures prepared from beta 2 KO mice) failed to prevent A beta-induced toxicity. In SH-SY5Y cells, larger aggregates of A beta preferentially up-regulated alpha 7-nAChR expression and function accompanied by a significant decrease in cell viability. Co-treatment MLA, but not mecamylamine (MEC), prevented All exposure-induced neurotoxicity. Our results suggest a detrimental role of upregulated alpha 7-nAChRs in the mediation of A beta-induced neurotoxicity. (C) 2015 Elsevier Ltd. All rights reserved.