BIOMETALS, OXIDATIVE STRESS, AND AB AMYLOIDOSIS

描述(摘自申请人摘要)：令人信服的证据表明 生物金属(铁、铜、锌)的动态平衡失调和氧化应激 参与AD的Aβ淀粉样蛋白病理的神经化学因素。这个 候选人在体外发现，它们可以促进聚集和氧化 Abeta多肽的修饰，最近的报告表明淀粉样斑块 在死后AD的脑组织中，这些生物金属明显丰富。 相反，用螯合剂从死后AD脑中去除这些金属 标本会导致Aβ淀粉样斑块溶解。最近， 候选人发现Abeta和铜(II)之间新的氧化还原相互作用， 在较小程度上，Fe(III)会产生还原的金属离子， 铜(I)和铁(II)，以及由此产生的活性氧物种 (ROS)-过氧化氢(H_2O_2)和羟基自由基(OH)。这些异常 相互作用可能会导致在AD中观察到的大脑氧化损伤。 此外，研究还表明，过氧化氢介导了Aβ细胞毒性， 增强细胞APP的表达，增加Abeta的产生，这意味着 淀粉样变性和氧化应激之间的恶性循环。因此， 候选假设：生物金属(铁、铜和锌)和 氧化应激增强了AD的病理。为了检验这一假设， 申请者计划：(I)评估膳食金属补充剂的影响 铁、铜、锌与膳食硫胺素引起的氧化应激 缺乏，对Aβ淀粉样蛋白病理和非淀粉样蛋白病理使用 APP2576小鼠；(Ii)评价氧化还原活性铁和铜对Aβ的影响 原代培养神经元的神经毒性；(Iii)测定脑组织中的过氧化氢 体内微透析法测定伴随Aβ淀粉样变性的水平。这些数据 将促进我们对生物金属在体内的生物化学作用的理解 代谢紊乱和氧化应激在AD病理中的作用 理解金属络合潜力的科学基础和 阿尔茨海默病的抗氧化疗法。

DESCRIPTION (From the Applicant's Abstract): Compelling evidence has indicated that dyshomeostasis of biometals (Fe, Cu, Zn) and oxidative stress are neurochemical factors that participate in Abeta amyloid pathology of AD. The candidates found in vitro that they could promote aggregation and oxidative modifications of Abeta peptides, and recent reports show that amyloid plaques in post-mortem brain tissue of AD are markedly enriched in these biometals. Conversely, removal of these metals with chelators from post-mortem AD brain specimen causes the Abeta amyloid plaques to dissolve. More recently, the candidates discovered that novel redox interactions between Abeta and Cu(II), and to a lesser extent, Fe(III), engender production of reduced metal ions, Cu(I) and Fe(II), and the consequent generation of reactive oxygen species (ROS)-hydrogen peroxide (H2O2) and hydroxyl radical (OH). These abnormal interactions may lead to the brain oxidation damage that is observed in AD. Moreover, studies have also shown that H2O2 mediates Abeta cellular toxicity, enhances cellular APP expression, and heightens Abeta production, implicating a vicious cycle between Abeta amyloidosis and oxidative stress. Hence, the candidates hypothesize: Dysregulation of biometals (Fe, Cu, and Zn) and oxidative stress potentiate AD pathology. To test the hypothesis, the applicants plan to: (i) assess the impact of dietary metal supplementation with Fe, Cu and Zn, as well as oxidative stress induced by the dietary thiamine deficiency, upon Abeta amyloid pathology and non-amyloid pathology using APP2576 mice; (ii) to evaluate effects of redox-activ Fe and Cu on Abeta neurotoxicity using primary neuronal culture; (iii) to determine cerebral H2O2 levels accompanying Abeta amyloidosis using in vivo microdialysis. These data will advance our understanding of in vivo biochemical roles of biometal dyshomeostasis and oxidative stress in AD pathology, and provide a firm scientific base for understanding the potential of metal chelation and antioxidant therapies for AD.