Cellular trafficking of pathogenic Abeta seeds in vitro and in vivo

描述（由申请人提供）：阿尔茨海默病（AD）是老年人痴呆症的最常见原因，目前约有500万美国人患有此病。最近的研究表明，阿尔茨海默病的一个重要特征是大脑中特定蛋白质的异常积聚，而蛋白质A¿的聚集是主要事件。然而，这种聚集过程是如何开始的，以及聚集物是如何从一个地区传播到另一个地区的，仍然不确定。我们的研究目标是了解启动阿尔茨海默病发病机制的细胞和分子过程。我们之前的研究发现，通过输注含有聚集A¿的稀释的富含A¿的脑提取物，可以在AD转基因小鼠模型中诱导或播种A¿的沉积。最近，我们发现可以通过向小鼠腹腔注射富含A¿的脑提取物来播种A¿聚集。初步数据表明单核吞噬细胞（巨噬细胞）是种子的载体，因为携带A¿-种子的巨噬细胞在腹腔注射种子后进入循环。然而，尚无直接证据证明种子是如何通过细胞运输进入大脑的。本项目的目的是通过转基因小鼠模型和巨噬细胞处理种子的体外模型来阐明巨噬细胞在传播A¿聚集种子中的作用。在绝大多数AD病例中，沉淀蛋白聚集的因素仍然未知。了解诱导A¿聚集和扩散的细胞机制，可能最终为阿尔茨海默病和其他老年人脑部疾病的新疗法指明道路。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in aging humans, currently afflicting approximately 5 million Americans. Research recently has shown that an important feature of AD is the abnormal accumulation of specific proteins in the brain, and that the aggregation of the protein A¿ is a primary event. However, how this process of aggregation is initiated, and how the aggregates spread from one region to another, remains uncertain. The goal of our research is to understand the cellular and molecular processes that initiate the pathogenesis of AD. Our previous studies found that the deposition of A¿ can be induced, or seeded, in the brains of transgenic mouse models of AD by the infusion of dilute, A¿-rich brain extracts containing aggregated A¿. Very recently we found that A¿ aggregation can be seeded by injections of A¿-rich brain extracts into the abdominal cavity of mice. Preliminary data implicate mononuclear phagocytes (macrophages) as the vectors of the seeds, in that A¿-seed- laden macrophages enter the circulation following the intraperitoneal injection of seed. However, direct evidence for the cellular transport of the seeds into the brain is lacking. The objective of this project is to clarify the role of macrophages in disseminating the seeds for A¿ aggregation using a transgenic mouse model and in vitro models of the processing of seeds by macrophages. In the vast majority of AD cases, the factors that precipitate protein aggregation remain unknown. Understanding the cellular mechanisms underlying induced A¿ aggregation and spread could eventually point the way to new therapies for Alzheimer's disease and other debilitating brain disorders of the elderly.