Peripheral sequestration of abeta on transport systems

描述（由申请人提供）：在阿尔茨海默病的发病机制中，外周和中枢神经系统的 A/3 水平之间相互依赖的想法是相当新的。使用抗 A/3 抗体进行免疫治疗导致外周 A/3 显着增加的观察结果构成了 Dave Holtzman 提出的外周库假说的基础。我们自己的实验室随后观察到了对 A/3 的外周效应，无论是抗体介导的隔离还是使用其他外周 A/3 结合剂 (PABBA)，例如不会进入大脑的凝溶胶蛋白。事实上，还没有任何出版物显示外围隔离在任何实验范式下的工作机制。 A/3 可以通过被动整体流动或主动运输在大脑和外周之间转移。该提案旨在检查这两个系统中的哪一个受到凝溶胶蛋白介导的外周隔离的影响，以及在存在或不存在聚集淀粉样蛋白的情况下特定脑区室中 A/3 的动态通量。这项工作将扩展我们发表的观察结果，提供机制证据，证明这种新颖的治疗方法值得进一步开发，并且通过确定哪些系统受到影响，它将把努力转向可开发用于临床用途的新靶标。

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.