| Project/Area Number |
09044288
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
UEDA Kunihiro KYOTO UNIVESITY,INSTITUTE FOR CHEMICAL RESEARCH,PROFESSOR, 化学研究所, 教授 (00027070)
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| Co-Investigator(Kenkyū-buntansha) |
SAMOCHOCKI M ポーランド科学アカデミー, 医学研究センター, 助手
STROSZNAJDER ジョアンナ ポーランド科学アカデミー, 医学研究センター, 教授
TANAKA Seigo KYOTO UNIVESITY,INSTITUTE FOR CHEMICAL RESEARCH,ASSOCIATE PROFESSOR, 化学研究所, 助教授 (70263150)
MAREK Samochocki POLISH ACADEMY OF SCIENCES,MEDICAL RESEARCH CENTRE,ASSISTANT PROFESSOR
JOANNA Strosznajder POLISH ACADEMY OF SCIENCES,MEDICAL RESEARCH CENTRE,PROFESSOR
安達 善文 京都大学, 化学研究所, 助手 (50201893)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1997: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Alzheimer's disease / Abeta amyloid / apoptosis / NAC / poly (ADP-ribose) synthetase / nitric oxide (NO) / NO synthetase (NOS) / NMDA receptor / PC12細胞 / NO(一酸化窒素) / NOS(NO合成酵素) / α-シヌクレイン / ポリ(ADP-リボース) / PARS |
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| Research Abstract |
1. Analysis of Mechanism of Neuronal Death Caused by Abeta Amyloid (the Japanese Group)
(1)Induction of neuronal death by Abeta amyloid
The 25-35 fragment of Abeta peptide (Abeta25-35) proved to be toxic in differentiated PC 12 cells at a concentration of 100 nM.Part of the cells showed chromatin aggregation and DNAfragmentation, suggesting that neuronal death in the brain of Alzheimer's disease (AD) is caused, at least partly, by apoptosis.
(2)Promotion of Abeta amyloid formation by NAC
NAC (Non-Abeta component of AD amyloid) was shown to be as amyloidogenic and neurotoxic as Abeta25-35 peptide and also promotive of Abeta aggregation. This result suggests that the coexistence of Abeta and ANC peptides facilitates amyloid formation and enhances neuronal injury.
(3)Implication of poly(ADP-ribose) synthetase (PARS) in neuronal death Abeta amyloid induced initial activation of PARS, followed by rapid inactivation) This change suggests a relationship between the activity , change and the cleavage of PARS during neuronal injury by Abeta amyloid.
2. Studies on Role of Nitric Oxide (NO) in Neuronal Death (the Polish Group)
The mechanism of neurotoxicity of Abeta amyloid was analyzed with
reference to intracellular signaling, particularly the NO cascade. The activity of NMDA recepter-mediated and Ca^<2+>/calmodulin-dependent NOS (nitric oxide synthase) was lower in the hippocampus and cerebellum in aged rat. Afbeta25-35 had no effect on the NOS activity in the basal condition, but reduced NMDA-responsive NOS activation. These results suggest the possibility that Abeta amyloid interferes with the intracellular signaling of NO cascade induced by NMDA.
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