Studies on mechanisms of neurodegeneration by Abeta-amyloid

1.Aβ淀粉样蛋白致神经元死亡机制分析(日本组)(1)Aβ淀粉样蛋白诱导的神经元死亡Abeta25-35片段(Abeta25-35)在100 nM的浓度下对分化的PC 12细胞有毒性，部分细胞显示染色质聚集和DNA断裂，提示阿尔茨海默病(AD)脑内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Abeta成分)促进Abeta淀粉样蛋白的形成与Abeta25-35肽和Abeta25-35肽一样具有致淀粉样和神经毒性作用。这一结果表明，Abeta和ANC肽的共存促进了淀粉样蛋白的形成并加强了神经元的损伤。(3)聚(ADP-核糖)合成酶(PARS)在神经元死亡中的意义Abeta淀粉样蛋白诱导了PARS的初始激活，随后迅速失活)这种变化表明Abeta淀粉样蛋白在神经元损伤过程中PARS的活性、变化和裂解之间的关系。一氧化氮(NO)在神经元死亡中的作用研究(波兰组)Aβ淀粉样蛋白的神经毒性机制从细胞内信号转导，特别是NO级联反应的角度进行了分析。老年大鼠海马区和小脑区NMDA受体介导的一氧化氮合酶活性和钙/钙调素依赖的一氧化氮合酶活性降低。Afbeta25-35对基础状态下的一氧化氮合酶活性无影响，但降低了NMDA反应性一氧化氮合酶活性。这些结果表明，Aβ淀粉样蛋白可能干扰了NMDA诱导的NO级联反应的细胞内信号转导。

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.