Peripheral sequestration of abeta on transport systems

描述（由申请人提供）：外周和中枢神经系统A/3水平在阿尔茨海默病发病机制中的相互依存关系是相当新的想法。观察到抗a /3抗体免疫治疗导致外周a /3显著增加，形成了Dave Holtzman提出的外周汇假说的基础。我们自己的实验室随后对a /3的外周效应进行了观察，包括抗体介导的隔离和使用其他外周a /3结合剂（PABBAs），如凝胶胶，这些外周a /3结合剂不会进入大脑。实际上，没有任何发表的文章表明，在任何实验范式下，外周封存是如何起作用的。A/3可以通过被动大流量或主动运输在脑和外周之间转移。本研究旨在研究在淀粉样蛋白聚集或不聚集的情况下，凝胶介导的外周隔离和特定脑区A/3的动态通量对这两种系统中的哪一种的影响。这项工作将扩展我们发表的观察结果，提供机制证据，证明这种新的治疗方法值得进一步发展，并且通过确定哪些系统受到影响，它将指导努力开发可用于临床应用的新靶点。

DESCRIPTION (provided by applicant): The idea of interdependence between peripheral and CNS levels of A/3 in the pathogenesis of Alzheimer's disease is fairly new. The observation that immunotherapy with anti-A/3 antibodies led to a significant increase in peripheral A/3 formed the basis of the peripheral sink hypothesis set forth by Dave Holtzman. Subsequent observations of a peripheral effect on A/3 was shown by our own lab, both for antibody-mediated sequestration and using other peripheral A/3 binding agents (PABBAs) such as gelsolin that does not cross into the brain. Virtually nothing has been published showing the mechanism by which peripheral sequestration works under any experimental paradigm. A/3 can be transferred between the brain and periphery either by passive bulk flow, or by active transport. This proposal aims to examine which of these two systems is impacted by gelsolin-mediated peripheral sequestration, and the dynamic flux of A/3 in specific brain compartments, in the presence, or absence of aggregated amyloid. This work will extend our published observations providing mechanistic evidence that this novel therapeutic approach is worthy of further development, and by identifying which systems are affected, it will direct efforts to new targets that could be developed for clinical use.