Cellular trafficking of B-amyloid seeds

描述（由申请人提供）：在转基因小鼠模型中淀粉样蛋白种子的细胞运输和阿尔茨海默样病理的诱导β -淀粉样蛋白（a¿）的聚集和脑内积累是已知最早的阿尔茨海默病的生物标志物。A¿的聚集是如何开始的以及异常蛋白质随后分散的方式仍然未知。最近的证据表明巨噬细胞参与了从外周到大脑的致病性A´´种子的摄取和运输，以及种子在大脑内定向传播的轴突运输。具体来说，我们的初步数据表明，在循环巨噬细胞中可以检测到腹腔注射的聚集性A¿，并且海马背侧注射的A¿可以选择性地在远离注射部位的大脑区域腹外侧内嗅皮层中播下A¿沉积。由于内嗅皮层和海马体是高度相互联系的，这一发现表明轴突运输可能负责种子从一个大脑区域到另一个大脑区域的运输，因此可以解释病理通过大脑的系统传播。然而，仍然没有直接证据表明这些机制将A¿种子贩运到大脑或在大脑内。该提议将验证巨噬细胞和神经元作为细胞特洛伊木马的假设，通过将致病蛋白种子引入远处的部位，在那里它们介导随后出现的病变。该项目的成功完成将有助于确定阿尔茨海默病治疗干预的新细胞和分子靶点，如蛋白质致病种子的摄取、加工、运输或细胞间转移。

DESCRIPTION (provided by applicant): Cellular trafficking of amyloid seeds and the instigation of Alzheimer-like pathology in a transgenic mouse model The aggregation and intracerebral accumulation of beta-amyloid (A¿) is the earliest known biomarker of Alzheimer's disease. How the aggregation of A¿ is initiated and the means by which the abnormal protein is subsequently dispersed remain unknown. Recent evidence has implicated macrophages in the ingestion and transport of pathogenic A¿ 'seeds' from the periphery to the brain, and axonal transport in the directed spread of the seeds within the brain. Specifically, our preliminary data demonstrate that aggregated A¿ injected intraperitoneally can be detected in circulating macrophages, and A¿ injected into the dorsal hippocampus can seed A¿ deposition selectively in the ventrolateral entorhinal cortex, a brain region that is distant from the injection site. Because the entorhinal cortex and hippocampus are highly interconnected, this finding suggests that axonal transport may be responsible for seed transport from one brain region to another, and thus may explain the systematic spread of pathology through the brain. However, there is still no direct evidence for the trafficking of A¿ seeds by these mechanisms to and within the brain. This proposal will test the hypothesis that macrophages and neurons act as cellular Trojan horses by introducing pathogenic protein seeds into distant sites, where they mediate the subsequent emergence of lesions. Successful completion of this project will help to identify new cellular and molecular targets for therapeutic intervention in Alzheimer's disease, such as the uptake, processing, transport, or intercellular transfer of proteopathic seeds.