The blood-brain barrier and Alzheimer pathology

项目摘要 血管血脑屏障功能障碍和脑血管渗漏 在衰老和阿尔茨海默病(AD)中存在，并与 临床前轻度认知障碍。根据最近的发现，我们已经定义了一个高度 直接导致神经功能障碍和认知功能障碍的解释性生物途径 在血脑屏障功能障碍之后。虽然直觉上认为基础血管功能的丧失 保护大脑的接口预计会导致神经并发症， 可能导致AD，以前还没有明确定义的BBB联系机制 功能障碍转化为AD病理。人类的现有数据受到与可能的 血脑屏障渗漏的区域差异及血脑屏障破坏的时间特征 尤其是与阿尔茨海默病相关的两种蛋白质的沉积 -淀粉样蛋白(A-)的发病机制和Tau的病理聚集物。 很少有研究研究这些病理蛋白与血脑屏障之间的关系。 没有探索四种截然不同的情况：(1)没有 阿尔茨海默病病理蛋白与血脑屏障破坏的关系(二)血脑屏障破坏所致 增加这些蛋白质的积累或(3)增加这些蛋白质的积累 导致血脑屏障中断。(4)AD蛋白病理与血脑屏障破坏形成正反馈 起源于任一项并通过加剧传输/传播相关的环路 由血脑屏障破坏造成的条件造成的蛋白质病理。 在这项研究中，我们将结合认知正常人类的描述性纵向数据 正电子发射计算机断层扫描获得Tau和A测量及动态对比增强 磁共振成像(DCE-MRI)以获得BBB测量，研究在 我们将在其中操纵血脑屏障的AD转基因小鼠模型。这些研究将结合在一起 解剖个体的小鼠模型中AD发病机制的探讨 分别处理血脑屏障破坏、淀粉样蛋白和tau蛋白的贡献，以及人类 将这些基本发现转化为对人类衰老和健康状况的观察的研究 临床前AD。

Project Abstract Dysfunction of the vascular blood-brain barrier (BBB) and cerebrovascular leakiness are present during aging and in Alzheimer's disease (AD) and are associated with the onset of preclinical mild-cognitive impairment. Based on recent discoveries we have defined a highly explanatory biological pathway that directly causes neural dysfunction and cognitive impairment following BBB dysfunction. While it is intuitive that loss of function of the fundamental vascular interface that protects the brain would be expected to cause neurological complications that may contribute to AD, previously there has not been a clearly defined mechanism linking BBB dysfunction to AD pathology. Existing data in humans suffer from limitations related to possible regional differences in BBB leakage and the temporal characteristics of BBB disruption particularly in relation to the deposition of the two proteins that have been implicated in AD pathogenesis, -amyloid (A) and pathological aggregates of tau. Very few studies have examined how these pathological proteins are related to BBB disruption, and there is no exploration of the four crucially different scenarios: (1) that there is no relationship between AD pathological proteins and BBB disruption (2) that BBB disruption leads to increased accumulation of these proteins or (3) that increased accumulation of these proteins leads to BBB disruption. (4) AD protein pathologies and BBB disruption form a positive feedback loop that originates with either and are related via the exacerbation of transmission/spread of protein pathologies by conditions created by BBB disruption. In this study we will combine descriptive longitudinal data in cognitively normal humans using PET scanning to obtain tau and A measurements and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to obtain BBB measurements, with studies in transgenic mouse models of AD where we will manipulate the BBB. Together these studies will probe mechanisms of AD pathogenesis in mouse models that enable dissecting the individual contributions of BBB disruption, amyloid and tau by manipulating each separately, and human studies that translate these basic findings to observations in the human situation of aging and preclinical AD.