A novel nicotinic mechanism underlies β-amyloid-induced neurotoxicity

• Published in: Neuropharmacology 2015-10, Vol.97, p.457-463
• Main Authors: Liu, Qiang, Xie, Xitao, Emadi, Sharareh, Sierks, Michael R., Wu, Jie
• Format: Article
• Language: English
• Subjects: Aconitine - analogs & derivatives; Aconitine - pharmacology; AD, Alzheimer disease; alpha7 Nicotinic Acetylcholine Receptor - genetics; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Amyloid beta-Peptides - toxicity; Animals; Aβ, amyloid-β; BFCN, basal forebrain cholinergic neurons; Cell Line, Tumor; Cells, Cultured; Dihydro-beta-Erythroidine - pharmacology; Dose-Response Relationship, Drug; Hippocampus - drug effects; Hippocampus - physiopathology; Humans; Immunoprecipitation; L-Lactate Dehydrogenase - metabolism; Mecamylamine - pharmacology; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Atomic Force; Neurons - drug effects; Neurons - physiology; Neuroprotective Agents - pharmacology; Nicotinic Antagonists - pharmacology; Patch clamp; Patch-Clamp Techniques; Receptors, Nicotinic - genetics; Receptors, Nicotinic - metabolism; α7-nAChRs, α7-containing nicotinic acetylcholine receptors
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.04.025

Loss of basal forebrain cholinergic neurons (BFCN) correlates with cognitive deficits in Alzheimer disease (AD). Our recent evidence suggests that chronic exposure to Aβ up-regulated neuronal α7-nAChRs and increased neuronal excitability in cultured hippocampal neurons. However, the impact of the up-regulated α7-nAChRs on Aβ-induced neurotoxicity remains unclear. In this study, we investigated the role of α7-nAChRs in the mediation of Aβ-induced neurotoxicity. The effects of Aβ exposure on α7-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 α7-nAChRs are necessary for Aβ-induced neurotoxicity in hippocampal neurons because chronic Aβ significantly increased LDH level in hippocampal cultures, which was prevented by either α7-nAChR antagonist methyllycaconitine (MLA) or by α7 subunit gene deletion (cultures prepared from nAChR α7 subunit KO mice), whereas β2-containing nAChR antagonist (dihydro-β-erythroidine, DhβE) or the genetic deletion of nAChR β2 subunit (cultures prepared from β2 KO mice) failed to prevent Aβ-induced toxicity. In SH-SY5Y cells, larger aggregates of Aβ preferentially up-regulated α7-nAChR expression and function accompanied by a significant decrease in cell viability. Co-treatment MLA, but not mecamylamine (MEC), prevented Aβ exposure-induced neurotoxicity. Our results suggest a detrimental role of upregulated α7-nAChRs in the mediation of Aβ-induced neurotoxicity. •α7-nAChRs are necessary for chronic Aβ-induced neurotoxicity in hippocampal cultures.•Chronic Aβ exposure up-regulates α7-nAChR function in cholinergic cells.•Chronic Aβ exposure up-regulates surface expression of α7-nAChRs in cholinergic cells.•Co-treatment with MLA prevents chronic Aβ exposure-induced neurotoxicity in cholinergic cells.