title: Molecular characterization of neurohybrid cell death induced by Alzheimer's amyloid-beta peptides via p75NTR/PLAIDD.
abstract: One of the most important pathological features of Alzheimer's disease (AD) is extracellular senile plaques, whose major component is amyloid-beta peptides (Abeta). Abeta binds to the extracellular domain of p75NTR (p75 neurotrophin receptor) and induces neuronal cell death. We investigated the molecular mechanism of Abeta-induced neurotoxicity in detail from the standpoint of interaction between p75NTR and its recently identified relative, PLAIDD (p75-like apoptosis-inducing death domain). Using F11 neuronal hybrid cells, we demonstrate that there are two distinct pathways for Abeta-induced toxicity mediated by p75NTR. One pathway that has been previously elucidated, is mediated by p75NTR, Go, JNK, NADPH oxidase and caspase3-related caspases. We found that PLAIDD and Gi proteins, heterotrimeric G proteins, are involved in the alternative Abeta-induced neurotoxicity mediated by p75NTR. The alternative pathway triggered by Abeta is thus mediated by p75NTR, PLAIDD, Gi, JNK, NADPH oxidase and caspase3-related caspases. In addition, we found that HN, ADNF, IGF-I, or bFGF inhibits both pathways of Abeta-induced neurotoxicity mediated by p75NTR.
authors.affiliation: Department of Pharmacology, KEIO University School of Medicine, Shinanomachi, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Emi
authors.initials: E
authors.lastname: Tsukamoto
authors.forename: Harald
authors.initials: H
authors.lastname: Frankowski
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kouyama
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kita
authors.forename: Takako
authors.initials: T
authors.lastname: Niikura
authors.forename: Sadakazu
authors.initials: S
authors.lastname: Aiso
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nishimoto
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism; D006822:Hybrid Cells; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D019255:NADPH Oxidases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D011506:Proteins / Q000494:pharmacology; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C470601:Nradd protein, rat; D010446:Peptide Fragments; D011506:Proteins; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; C075222:amyloid beta-protein (1-42); C427211:humanin; D019255:NADPH Oxidases; D037342:Pertussis Toxin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go