title: [Possible mechanisms of A beta(1-40)- or A beta(1-42)-induced cell death and their rescue factors].
abstract: Amyloidbetapeptide (A beta) is implicated in neuronal cell death in Alzheimer's disease, but the molecular mechanisms are still unclear. We analyzed its mechanism and found several potential rescue factors against A beta-mediated apoptosis. A beta(1-40) stimulated phosphorylation of tau and JNK and induced cell death in SH-SY5Y cells. The cell death was inhibited by insulin-like growth factor-1, suggesting that the JNK pathway may be involved in A beta(1-40)-induced cytotoxicity. Using the human fetus brain cDNA library-targeted differential display technique, a new gene BF5-1 (32aa) was found as a rescue factor against A beta(1-40). BF5-1 has partially the same amino acid sequences as those of the C-terminus of cytochrome c oxidase subunit VIIb (COX-VIIb). COX-VIIb mRNA is increased in AD brains and its overexpression in cells enhanced A beta(1-40)-toxicity. These data suggest that BF5-1 may act as a dominant negative mutant of COX-VIIb. A beta(1-42) also induced cell death in rat neuroblastoma B104 cells, which was abolished by addition of IL-11. By cDNA subtraction analysis in the cell death, the enhanced expression of L-phosphoserine phosphatase was found, but this was also abolished by IL-11. The glutamate neurotoxicity was stimulated in the presence of D-serine, suggesting that NMDA receptors may be involved in A beta(1-42)-induced cytotoxicity. A beta(1-42) also induced increase of a new gene p18A beta rP (p18-amyloid-beta-responsive protein; 166 aa) mRNA expression; overexpression of this gene in PC12 cells induced cell death. By the application of a death trap method, a new gene, p60TRP (p60-Transcription-Regulating-Protein; rat:539 aa, human:547aa), was found as a potential rescue factor against the cell death by p18A beta rP. Thus, our cell death systems and/or new rescue proteins may provide suitable tools for the establishment of drug screening systems leading to the identification of new low-molecular candidates applicable for the treatment of AD.
authors.affiliation: BF Research Institute, Inc., c/o National Cardiovascular Center. Nagai_Yasuo@takeda.co.jp
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Nagai
authors.forename: Aichi
authors.initials: A
authors.lastname: Ogasawara
authors.forename: Klaus
authors.initials: K
authors.lastname: Heese
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins / Q000502:physiology*; D003576:Electron Transport Complex IV / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D017370:Interleukin-11 / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D010446:Peptide Fragments / Q000502:physiology*; D010766:Phosphorylation; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled
chemical_list: D016229:Amyloid beta-Peptides; D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D003576:Electron Transport Complex IV; D007334:Insulin-Like Growth Factor I; D017370:Interleukin-11; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D010446:Peptide Fragments; D021122:Protein Subunits; D011506:Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; C496842:GPRASP3 protein, human; D043562:Receptors, G-Protein-Coupled; C496843:COX7B protein, human; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)