ALUMINUM INDUCED INTERACTIONS AND NEUROLOGICAL DISEASE

描述：（申请人的摘要）铝长期以来一直被怀疑 在一些与衰老有关的神经系统疾病中发挥作用， 但这种联系从未明确确立。有 有证据表明铁对增强自由基的潜力 神经组织中的生成被铝增强，尽管这 后一种金属没有固有的助氧化剂性质。的意图 本申请旨在阐明潜在的分子机制， 这样的增强可以通过其发生。螯合作用或 在它们相互作用时， 考察对这种氧化应激反应的生物基质 将寻求由组合金属引起的。的性质 诱导的活性氧将使用酶和 电子自旋共振技术。随后，生物 将在动物中研究铝-铁相互作用的相关性 暴露于这些金属单独或组合。浓度 这些金属在不同的大脑区域将被量化的原子 吸收 试图将铝的水平和氧化参数联系起来， 来自老年人和阿尔茨海默氏症患者大脑的人类死后脑组织将 也可以做。除了研究与氧化有关的参数外， 给药动物中蛋白质和膜稳定性的损伤，以及 治疗的胆碱能神经母细胞瘤细胞，关键蛋白如泛素， β-淀粉样蛋白和热休克蛋白HSP 70，将通过 免疫程序。计划研究的最后阶段是 尝试减轻体外神经组织中诱导的变化， 这些金属化合物在体内的作用。这将涉及饮食 补充抗氧化维生素或使用选择性的 螯合剂。结果将阐明铝可能发挥的作用， 增强与年龄相关的神经系统疾病。

DESCRIPTION: (Applicant's Abstract) Aluminum has been long suspected to play a role in several neurological diseases associated with aging, but this linkage has never been unequivocally established. There is evidence that the potential of iron for enhancing free radical generation in nervous tissue is enhanced by aluminum, although this latter metal has no intrinsic pro-oxidant properties. The intent of this application is to illuminate the underlying molecular mechanisms by which such a potentiation may take place. The effect of chelation or protein sequestration of either metal upon their interactions will be examined. The biological substrate responsive to such oxidative stress induced by the combined metals, will be sought. The nature of the induced reactive oxygen species will be documented using both enzymic and electron spin resonance techniques. Subsequently, the biological relevance of aluminum-iron interactions will be investigated in animals exposed to these metals singly or in combination. The concentrations of these metals in various brain regions will be quantitated by atomic absorption. An attempt to correlate levels of aluminum and oxidative parameters in human post-mortem cerebral tissue from aged and Alzheimer's brains will also be made. In addition to study of parameters relating to oxidative damage to proteins, and membrane stability in dosed animals, and in treated cholinergic neuroblastoma cells, key proteins such as ubiquitin, beta-amyloid, and heat shock protein HSP 70, will be quantitated by immunological procedures. The final phase of the planned research is an attempted mitigation of changes induced in neural tissue in vitro and in vivo by these combined metals. This will involve dietary supplementation with antioxidant vitamins or the use of selective chelators. Results will illuminate the role that aluminum may play in potentiation of age-related neurological diseases.