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Studies on mechanisms of neurodegeneration by Abeta-amyloid

Aβ淀粉样蛋白神经退行性变机制的研究

基本信息

批准号：
09044288
负责人：
UEDA Kunihiro
金额：
$ 2.5万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

1. Analysis of Mechanism of Neuronal Death Caused by Abeta Amyloid (the Japanese Group)(1)Induction of neuronal death by Abeta amyloidThe 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 NACNAC (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 withreference 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.

1. A β淀粉样蛋白致神经元死亡的机制分析（日本组）（1）A β淀粉样蛋白诱导神经元死亡A β肽的25-35片段（Abeta 25 -35）在100 nM的浓度下在分化的PC 12细胞中被证明是有毒的。部分细胞显示染色质聚集和DNA片段化，提示阿尔茨海默病（AD）脑中的神经元死亡至少部分是由细胞凋亡引起的。（2）NACNAC（AD淀粉样蛋白的非A β组分）促进A β淀粉样蛋白形成显示出与A β 25 -35肽一样的淀粉样蛋白生成和神经毒性，并且还促进A β聚集。该结果表明，Abeta和ANC肽的共存促进淀粉样蛋白形成并增强神经元损伤。（3）多聚腺苷二磷酸核糖合成酶（PARS）在神经元死亡中的意义A β淀粉样蛋白诱导PARS的初始激活，随后迅速失活）这一变化表明A β淀粉样蛋白损伤神经元时PARS的活性、变化和裂解之间的关系.一氧化氮（NO）在神经元死亡中作用的研究（波兰组）通过细胞内信号转导，特别是NO级联反应，分析了A β淀粉样蛋白的神经毒性机制。老年大鼠海马和小脑NMDA受体介导的和Ca^2+/钙调素依赖的NOS活性降低。Afbeta 25 -35在基础条件下对NOS活性没有影响，但降低了NMDA响应性NOS激活。这些结果提示，A β淀粉样蛋白可能干扰NMDA诱导的NO级联反应的细胞内信号传导。