STRUCTURAL/KINETIC ANALYSIS OF ABETA FIBRILLOGENESIS

一组日益多样化和引人注目的实验观察 支持这样一种假设，即Abeta纤维化启动了一系列 最终导致AD的事件。尽管人们已经知道了很多关于 斑块中Abeta的一级结构及其核心附近的次级结构 Abeta在纤维中的结构，对其机制知之甚少 新生的Abeta通过这种方式折叠并组装成纤维。鉴定 纤维形成中间体的表征和测定 如果深思熟虑、有重点的话，Aβ纤维形成的动力学是至关重要的。 将努力开发影响人类健康的治疗剂 纤维形成过程。这一领域的信息性研究不仅将 显著加快AD药物发现的步伐，但也将 推进了解和治疗其他淀粉样变性的努力。我们的长期计划 目标是通过一系列三个步骤来检验上述假设：1) 从分子水平详细阐明Aβ纤维形成的机制；2) 开发能够阻断或逆转关键步骤的化学试剂 体外纤维形成途径；3)配制和临床应用 测试在体外开发的试剂的效果。这项提案将重点放在 关于长期目标1.提出的三个具体目标建立在一些基础上 令人兴奋的最新实验发现。其中包括发现了 潜在的新治疗靶点--淀粉样原纤维：进展 一种强大的范例，使用准弹性光散射光谱， 用于定量分析Aβ纤维形成动力学；以及 一种新的Abeta折叠中间体的鉴定及其研究 可以提供有关Abeta早期阶段的重要信息 纤维形成。

An increasingly diverse and compelling set of experimental observations supports the hypothesis that Abeta fibrillization starts a cascade of events which eventually results in AD. Although much is known about the primary structure of Abeta in plaques and about the core secondary structure of Abeta in fibrils, little is understand about the mechanisms by which nascent Abeta folds and assembles into fibrils. Identification and characterization of fibrillogenesis intermediates and determination of the kinetics of Abeta fibrillogenesis is crucial if thoughtful, focused efforts are to be made to develop therapeutic agents affecting the fibrillogenesis process. Informative studies in this area will not only significantly accelerate the pace of drug discovery for AD, but will also advance efforts to understand and treat other amyloidoses. Our long term goal is to test the above hypothesis in a series of three steps: 1) to elucidate in molecular detail the mechanisms in Abeta fibrillogenesis; 2) to develop chemical agents capable of blocking or reversing key steps in the fibrillogenesis pathway in vitro; and 3) to formulate and clinically test the efficacy of the agents developed in vitro. This proposal focuses on long term goal #1. The three specific aims proposed build on a number of exciting recent experimental findings. These include the discovery of a potential new therapeutic target, the amyloid protofibril: development of a powerful paradigm, using quasielastic light scattering spectroscopy, for the quantitative analysis of Abeta fibrillogenesis kinetics; and identification of a novel Abeta folding intermediate, the study of which could provide important information about the earliest stages of Abeta fibrillogenesis.