Peripheral sequestration of abeta on transport systems

阿尔茨海默病发病机制中外周和中枢神经系统A/3水平相互依赖的观点是相当合理的 新的。抗A/3抗体免疫治疗外周血淋巴细胞明显升高 A/3构成了Dave Holtzman提出的外周下沉假说的基础。随后的观察 我们自己的实验室显示了对A/3病毒的外围效应，包括抗体介导的隔离和使用 其他外周A/3结合剂(PABBA)，如明胶蛋白，不会进入大脑。虚拟 尚未发表任何关于外围设备自动减支在任何情况下工作的机制的文章 实验范式。 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。 这项建议旨在检查这两个系统中的哪一个受到明胶蛋白介导的外周细胞的影响 隔离，以及A/3在特定脑区的动态流量，在存在或不存在 聚集的淀粉样蛋白。这项工作将扩展我们发表的观察结果，提供机械证据 这种新的治疗方法值得进一步开发，并通过识别哪些系统是 我 受影响，它将把努力转向可以开发用于临床的新靶点。

The idea of interdependence between peripheral and CNS levels of A/3in the pathogenesis of AD 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/3was shown by our own lab, both for antibody-mediated sequestration and using other peripheral A/3binding 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 i affected, it will direct efforts to new targets that could be developed for clinical use.