title: A novel nicotinic mechanism underlies β-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 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.
authors.affiliation: Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA; Department of Neurology and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China. Electronic address: qliu@tijmu.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Biochemistry & Molecular Biology, Mayo Clinic, Scottsdale, AZ 85259, USA.
authors.forename: Xitao
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Chemical Engineering, Arizona State University, Tempe, AZ, USA.
authors.forename: Sharareh
authors.initials: S
authors.lastname: Emadi
authors.affiliation: Department of Chemical Engineering, Arizona State University, Tempe, AZ, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sierks
authors.affiliation: Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA; Department of Physiology, Shantou University of Medical College, Shantou, Guangdong, China. Electronic address: Jie.Wu@dignityhealth.org.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D047468:Immunoprecipitation; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008464:Mecamylamine / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018625:Microscopy, Atomic Force; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D000157:Aconitine; D016229:Amyloid beta-Peptides; D004079:Dihydro-beta-Erythroidine; D007770:L-Lactate Dehydrogenase; D008464:Mecamylamine; D018696:Neuroprotective Agents; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine
keywords: AD, Alzheimer disease; Aβ, amyloid-β; BFCN, basal forebrain cholinergic neurons; Patch clamp; α7-nAChRs, α7-containing nicotinic acetylcholine receptors