Blood-brain barrier dysfunction in Alzheimer's disease: from humans to animal models

项目概要/摘要： 现有文献表明，血脑屏障（BBB）的损伤复杂地参与了脑血管疾病的发生。 阿尔茨海默病和相关痴呆（ADRD）的发病机制。例如， 表明ADRD脑的特征是血液来源的蛋白质的积累， BBB特异性细胞和血管内皮损伤。然而，血脑屏障损伤与 痴呆症的病理标志如β-淀粉样蛋白、tau蛋白和脑小血管疾病并不清楚， 理解，特别是在人类。这主要是由于缺乏体内技术来评估 BBB功能。PI是微血管功能非侵入性成像的领先专家，他的实验室 最近开发、优化和验证了一种MRI技术，用于评估BBB对水的渗透性 分子。我们使用这种新技术的初步研究表明，强有力的证据表明：1）显著 使用非对比MRI可以在轻度认知障碍（MCI）患者中检测到BBB崩溃; 2） BBB破坏的程度与淀粉样蛋白负荷有关; 3）BBB功能可以预测认知功能， 功能，特别是在内存领域。 因此，本申请的中心目标是利用这些技术进步， BBB在MCI和早期痴呆中的破坏，并了解其与AD和小 血管病理学BBB对三种不同大小的分子，特别是水（分子量 18 g/mol）、钆MRI造影剂（分子量547 g/mol）和白蛋白（分子量66 K g/mol）将在相同的参与者中测量。人类患者研究将与动物研究并行 模型，以便临床相关的发现可以在实验模型中得到验证。炎症的作用 也将检查BBB分解。这些关系将在两个横截面和 纵向方式。这个多学科、多形式的项目有三个目标。目标1将审查 BBB破坏、淀粉样蛋白、tau病理学、小血管病理学和 125名老年参与者的炎症标志物，包括认知正常，MCI和早期痴呆。的 将在一个机制模型的框架内研究这些变量之间的相互关系。目标2将 对这些参与者进行30个月的随访，并调查BBB之间的纵向关系。 AD病理学、小血管病理学、炎症标志物和认知功能的分解和进展 功能最后，在目标3中，我们将使用以下方法验证ADRD中BBB功能障碍的病理基础： 我们的合作者分别为AD和小血管疾病开发了两种新型啮齿动物模型。 这些具有相对纯病理学的啮齿动物模型有望揭示更明确的关系 BBB破坏与AD和小血管病变之间的关系。

Project Summary/Abstract: Extant literature suggests that damage to the blood-brain barrier (BBB) is intricately involved in the pathogenesis of Alzheimer's disease and related dementia (ADRD). For example, post-mortem studies demonstrated that ADRD brain is characterized by the accumulation of blood-derived proteins, degeneration of BBB-specific cells, and injury of vascular endothelium. However, the relationship of BBB damage to pathological hallmarks of dementia such as beta-amyloid, tau, and cerebral small vessel disease are not well understood, particularly in humans. This is primarily attributed to a scarcity of in vivo techniques to evaluate BBB function. The PI is a leading expert in non-invasive imaging of microvascular function, and his laboratory has recently developed, optimized, and validated a MRI technique to assess BBB permeability to water molecules. Our preliminary studies using this novel technique has shown strong evidence that 1) Significant BBB breakdown can be detected in patients with mild cognitive impairment (MCI) using non-contrast MRI; 2) the extent of BBB breakdown is associated with amyloid burden; and 3) BBB function can predict cognitive function, particularly in the memory domain. The central goal of this application is therefore to capitalize on these technical advances and characterize BBB breakdown in MCI and early dementia, and to understand its causal relationship to both AD and small vessel pathology. BBB permeability to three molecules of different sizes, specifically water (molecular weight 18 g/mol), Gadolinium MRI contrast agent (molecular weight 547 g/mol), and albumin (molecular weight 66K g/mol) will be measured in the same participants. Human patient studies will be paralleled by studies in animal models so that clinically relevant discoveries can be validated in experimental models. The role of inflammation in BBB breakdown will also be examined. These relationships will be studied in both cross-sectional and longitudinal manner. This multi-modality, multi-disciplinary project has three Aims. Aim 1 will examine the cross-sectional relationship between BBB breakdown, amyloid, tau pathology, small vessel pathology, and inflammatory markers in 125 elderly participants including cognitively normals, MCI, and early dementia. The inter-relationships among these variables will be studied in the framework of a mechanistic model. Aim 2 will conduct a 30-month follow-up of these participants and investigate the longitudinal relationship between BBB breakdown and progression of AD pathology, small vessel pathology, inflammatory markers, and cognitive function. Finally, in Aim 3, we will validate the pathological underpinnings of BBB dysfunction in ADRD using two novel rodent models that our collaborators have developed for AD and small vessel disease, respectively. These rodent models with relatively pure pathology are expected to reveal more definitive relationships between BBB breakdown and AD and small vessel pathology.