title: Characterization of the toxic mechanism triggered by Alzheimer's amyloid-beta peptides via p75 neurotrophin receptor in neuronal hybrid cells.
abstract: Neuronal pathology of the brain with Alzheimer's disease (AD) is characterized by numerous depositions of amyloid-beta peptides (Abeta). Abeta binding to the 75-kDa neurotrophin receptor (p75NTR) causes neuronal cell death. Here we report that Abeta causes cell death in neuronal hybrid cells transfected with p75NTR, but not in nontransfected cells, and that p75NTR(L401K) cannot mediate Abeta neurotoxicity. We analyzed the cytotoxic pathway by transfecting pertussis toxin (PTX)-resistant G protein alpha subunits in the presence of PTX and identified that Galpha(o), but not Galpha(i), proteins are involved in p75NTR-mediated Abeta neurotoxicity. Further investigation suggested that Abeta neurotoxicity via p75NTR involved JNK, NADPH oxidase, and caspases-9/3 and was inhibited by activity-dependent neurotrophic factor, insulin-like growth factor-I, basic fibroblast growth factor, and Humanin, as observed in primary neuron cultures. Understanding the Abeta neurotoxic mechanism would contribute significantly to the development of anti-AD therapies.
authors.affiliation: Departments of Pharmacology and Anatomy, KEIO University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Tsukamoto
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Kanekura
authors.forename: Takako
authors.initials: T
authors.lastname: Niikura
authors.forename: Sadakazu
authors.initials: S
authors.lastname: Aiso
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nishimoto
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006822:Hybrid Cells; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D019255:NADPH Oxidases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides; D009842:Oligopeptides; D011506:Proteins / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D013002:Somatomedins / Q000378:metabolism; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009842:Oligopeptides; D011506:Proteins; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D013002:Somatomedins; C410622:activity-dependent neurotrophic factor; C427211:humanin; D016222:Fibroblast Growth Factor 2; D019255:NADPH Oxidases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins