The blood-brain barrier and Alzheimer pathology

项目摘要 血管血脑屏障（BBB）功能障碍和脑血管渗漏是 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，我们定义了一个高度 直接导致神经功能障碍和认知障碍的解释性生物途径 BBB功能障碍。虽然直觉上基本血管功能的丧失 保护大脑的接口预计会导致神经系统并发症， 可能有助于AD，以前没有明确定义的机制连接BBB 功能障碍转化为AD病理学。人类的现有数据受到与可能的 血脑屏障渗漏的区域差异和血脑屏障破坏的时间特征 特别是与AD相关的两种蛋白质的沉积有关 发病机制、β-淀粉样蛋白（A β）和tau的病理性聚集体。 很少有研究检查这些病理蛋白质如何与血脑屏障相关 破坏，并且没有探索四个至关重要的不同场景：（1）没有 AD病理蛋白与血脑屏障破坏的关系（2）血脑屏障破坏导致的AD病理蛋白与血脑屏障破坏的关系 增加这些蛋白质的积累或（3）增加这些蛋白质的积累 导致BBB中断。(4)AD蛋白病理学和BBB破坏形成正反馈 起源于任何一个并通过传播/传播的加剧而相关的循环 蛋白质病理学通过BBB破坏产生的条件。 在这项研究中，我们将联合收割机的描述性纵向数据在认知正常的人 使用PET扫描获得τ和Δ τ测量值，并进行动态对比增强 磁共振成像（DCE-MRI）以获得BBB测量值， AD的转基因小鼠模型，我们将在其中操纵血脑屏障。这些研究将 在能够解剖个体的小鼠模型中探索AD发病机制 通过分别操纵BBB破坏、淀粉样蛋白和tau蛋白， 将这些基本发现转化为人类衰老状况观察的研究， 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.