Cellular trafficking of B-amyloid seeds

描述(申请人提供)：淀粉样蛋白种子的细胞传输和在转基因小鼠模型中引发类似阿尔茨海默病的病理。β-淀粉样蛋白(A？)的聚集和在大脑中的积累是阿尔茨海默病最早的已知生物标志物。A？的聚集是如何开始的，以及随后异常蛋白是如何分散的，目前尚不清楚。最近的证据表明，巨噬细胞参与了致病种子从外周到大脑的摄取和运输，轴突运输参与了种子在大脑内的定向传播。具体地说，我们的初步数据表明，可以在循环中的巨噬细胞中检测到腹膜内注射的聚集A，并且注射到背侧海马区的A可以选择性地在远离注射部位的大脑腹外侧内嗅皮层沉积。由于内嗅皮层和海马体高度相连，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，从而可能解释病理通过大脑的系统性传播。然而，仍然没有直接证据表明这些机制将A种子运输到大脑和大脑内。这一提议将检验巨噬细胞和神经元作为细胞特洛伊木马的假设，将致病蛋白种子引入远程部位，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，例如蛋白质种子的摄取、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.