Defining the Properties of Pathogenic A-beta strains in AD

摘要/总结：项目3 国家卫生研究院的一个重要使命是减少慢性病对个人造成的严重损失， 家庭和社会。随着预期寿命的持续增长，阿尔茨海默病的幽灵越来越大 在美国和世界其他地区，但没有有效的预防或治疗这种疾病。到 为了克服这一障碍，必须了解阿尔茨海默病的基本生物学， 近年来在这方面取得了重大进展。例如，现在很明显， 阿尔茨海默病发病机制中的强制性事件是异常折叠的 蛋白质片段，称为Ablad 3。然而，令人惊讶的是，最近开发的用于对这些病变进行成像的方法， 活的大脑表明，一些患有大量阿尔茨海默病的人会变得痴呆，而另一些人则会 不要。换句话说，并不是所有的聚集体都对脑细胞有同样的毒性。本课题 我认为，Aesthetic的病理生物学特征是由多维结构的变化引起的 错误折叠的蛋白质。具体来说，我们假设，Ablation可以错误折叠和聚集成不同的形式，或 菌株，并且这些菌株控制分子的毒性。为了验证这一假设，我们建议：1） 研究确定菌株的聚集型AAE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的其他分子。 Aesthetic菌株的特征;和4）在Aesthetic病理学的转基因小鼠模型中复制Aesthetic菌株。通过 阐明了人类ApeA菌株的性质和多样性及其与疾病表型的关系， 本项目的目的是确定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 Aß. Surprisingly, however, recently developed methods for imaging these lesions in the living brain indicate that some people with large amounts of Aß pathology become demented, whereas others do not. In other words, not all aggregates of Aß appear to be equally toxic to brain cells. In this Project, we propose that the pathobiological characteristics of Aß result from variations in the multidimensional architecture of the misfolded protein. Specifically, we hypothesize that Aß 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 Aß 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 Aß strains; and 4) Replicate Aß strains in transgenic mouse models of Aß pathology. By clarifying the nature and diversity of human Aß 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.