Peripheral sequestration of abeta on transport systems

描述(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A/3水平之间的相互依赖的想法是相当新的。抗A/3抗体免疫治疗导致外周A/3显著增加的观察结果构成了Dave Holtzman提出的外周下沉假说的基础。我们自己的实验室随后观察到了A/3的外周效应，包括抗体介导的隔离和使用其他外周A/3结合剂(PABBA)，如不进入大脑的明胶。几乎没有发表过任何关于外周隔离在任何实验范式下起作用的机制的文章。A/3可以通过被动大量流动或主动运输在大脑和外周之间转移。这项建议旨在研究这两个系统中的哪个系统受到明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A/3的动态流量。这项工作将扩展我们发表的观察结果，提供机制证据，证明这种新的治疗方法值得进一步开发，并通过确定哪些系统受到影响，将努力指向可以开发用于临床的新靶点。

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.