Defining the Properties of Pathogenic A-beta strains in AD

摘要/摘要：项目3 美国国立卫生研究院的一项重要使命是减少慢性病对个人造成的深远影响， 家庭和社会。随着预期寿命的持续增长，阿尔茨海默氏症的幽灵越来越大 在美国和世界其他地区，还没有有效的预防或治疗这种疾病的方法。至 要克服这一障碍，就必须了解阿尔茨海默病的基本生物学，以及 近年来，在这方面取得了重要进展。例如，现在很明显，早期的 而阿尔茨海默病发病机制中的必备事件是异常折叠的积累 称为A？的蛋白质片段。然而，令人惊讶的是，最近开发出的对这些病变进行成像的方法 活着的大脑表明，一些带有大量A型病理的人会变得精神错乱，而其他人 不要这样做。换句话说，并不是所有的A？聚集体对脑细胞的毒性都是一样的。在这个项目中，我们 提出A型肺炎的病理生物学特征是多维结构变异的结果 错误折叠的蛋白质。具体地说，我们假设A可以错误折叠并聚合成不同的形式，或者 这些菌株控制着分子的毒性。为了验证这一假设，我们建议：1) 研究定义菌株的聚集A的分子和结构特征；2)确定如何 这些特征影响阿尔茨海默病的发病；3)识别细胞内影响阿尔茨海默病发病的其他分子 A？株的特性；4)在A？病理转基因小鼠模型中复制A？株。通过 阐明人类甲型流感病毒的性质和多样性及其与疾病表型的关系，这是 本项目的目的是寻找阿尔茨海默病的新分子治疗靶点。

ABSTRACT/SUMMARY: PROJECT 3 An important mission of the NIH is to reduce the profound toll that chronic diseases take on individuals, families, and society. As life expectancy continues to rise, the spectre of Alzheimer's disease looms ever larger over the US and the rest of the world, yet there is no effective preventive or treatment for the disorder. To overcome this obstacle, it is essential to understand the fundamental biology of Alzheimer's disease, and important strides have been made in this regard in recent years. It is now evident, for example, that an early and obligatory event in the pathogenesis of Alzheimer's disease is the accumulation of an abnormally folded protein fragment called A¿. Surprisingly, however, recently developed methods for imaging these lesions in the living brain indicate that some people with large amounts of A¿ pathology become demented, whereas others do not. In other words, not all aggregates of A¿ appear to be equally toxic to brain cells. In this Project, we propose that the pathobiological characteristics of A¿ result from variations in the multidimensional architecture of the misfolded protein. Specifically, we hypothesize that A¿ can misfold and aggregate into different forms, or strains, and that these strains govern the toxicity of the molecules. To test this hypothesis, we propose to: 1) Investigate the molecular and structural features of aggregated A¿ that define the strains; 2) Determine how these features affect the onset of Alzheimer's disease; 3) Identify other molecules within cells that influence the characteristics of A¿ strains; and 4) Replicate A¿ strains in transgenic mouse models of A¿ pathology. By clarifying the nature and diversity of human A¿ strains and their relationship to the disease phenotype, it is the objective of this project to identify new molecular therapeutic targets for Alzheimer's disease.