title: Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3β enzyme, β-amyloid and tau protein levels.
abstract: Cadmium is a neurotoxic compound which induces cognitive alterations similar to those produced by Alzheimer's disease (AD). However, the mechanism through which cadmium induces this effect remains unknown. In this regard, we described in a previous work that cadmium blocks cholinergic transmission and induces a more pronounced cell death on cholinergic neurons from basal forebrain which is partially mediated by AChE overexpression. Degeneration of basal forebrain cholinergic neurons, as happens in AD, results in memory deficits attributable to the loss of cholinergic modulation of hippocampal synaptic circuits. Moreover, cadmium has been described to activate GSK-3β, induce Aβ protein production and tau filament formation, which have been related to a selective loss of basal forebrain cholinergic neurons and development of AD. The present study is aimed at researching the mechanisms of cell death induced by cadmium on basal forebrain cholinergic neurons. For this purpose, we evaluated, in SN56 cholinergic mourine septal cell line from basal forebrain region, the cadmium toxic effects on neuronal viability through muscarinic M1 receptor, AChE splice variants, GSK-3β enzyme, Aβ and tau proteins. This study proves that cadmium induces cell death on cholinergic neurons through blockade of M1 receptor, overexpression of AChE-S and GSK-3β, down-regulation of AChE-R and increase in Aβ and total and phosphorylated tau protein levels. Our present results provide new understanding of the mechanisms contributing to the harmful effects of cadmium on cholinergic neurons and suggest that cadmium could mediate these mechanisms by M1R blockade through AChE splices altered expression.
authors.affiliation: Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, Avda. Puerta de Hierro s/n, 28040, Madrid, Spain. jdelpino@pdi.ucm.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Del Pino
authors.affiliation: Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041, Madrid, Spain.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Zeballos
authors.affiliation: Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041, Madrid, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Anadón
authors.affiliation: Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041, Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Moyano
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040, Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Díaz
authors.affiliation: Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041, Madrid, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García
authors.affiliation: Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040, Madrid, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Frejo
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019256:Cadmium Chloride / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D059329:Cholinergic Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018727:Muscarinic Antagonists / Q000633:toxicity*; D010766:Phosphorylation; D016548:Prosencephalon / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D034622:RNA Interference; D043643:Receptor, Muscarinic M1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D058851:GPI-Linked Proteins; C054369:MAPT protein, human; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D000110:Acetylcholinesterase; C548245:Ache protein, mouse; D019256:Cadmium Chloride
keywords: Acetylcholine esterase-R; Acetylcholine esterase-S; Aβ; Cadmium; GSK-3β; Muscarinic receptor M1; SN56 cells septal basal forebrain cholinergic neurons; Tau