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

阿尔茨海默病的血脑屏障功能障碍：从人类到动物模型

• 批准号: 10178195
• 负责人: Hanzhang Lu
• 金额: $ 236.82万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178195
• 关键词: Affect; Albumins; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Arterial Disorder; Autopsy; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Cerebral small vessel disease; Cerebrospinal Fluid; Cerebrum; Cognition; Cognitive; Contrast Media; Dementia; Dextrans; Disease model; Elderly; Enrollment; Event; Experimental Models; Functional disorder; Gadolinium; Goals; Human; Imaging Techniques; Impaired cognition; Individual; Inflammation; Interleukin-6; Laboratories; Literature; Magnetic Resonance Imaging; Measures; Memory; Microvascular Dysfunction; Modeling; Molecular Weight; Mus; Neuropsychological Tests; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Pathology; Patients; Permeability; Plasma; Process; Proteins; Rodent Model; Role; Serum Albumin; Smooth Muscle Myocytes; Study Section; Subcortical Infarctions; Subcortical Leukoencephalopathy; TNF gene; Techniques; Time; Transgenic Mice; Transgenic Organisms; Validation; Vascular Endothelium; Water; base; blood-brain barrier function; blood-brain barrier permeabilization; brain tissue; cell injury; cerebrovascular; clinically relevant; cognitive function; cytokine; follow-up; human disease; human model; human study; imaging biomarker; imaging study; in vivo; inflammatory marker; longitudinal design; mild cognitive impairment; mouse model; multidisciplinary; multimodality; non-invasive imaging; novel; tau Proteins; tau aggregation; tau-1; vascular injury; vascular risk factor; β-amyloid burden

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.

项目摘要/摘要： 现有的文献表明，血脑屏障(BBB)的破坏复杂地参与了 阿尔茨海默病和相关痴呆的发病机制。例如，尸检研究 证明了ADRD脑的特点是血源性蛋白的积聚，变性 血脑屏障特异性细胞与血管内皮细胞损伤。然而，血脑屏障损伤与 痴呆症的病理特征，如β-淀粉样蛋白、tau蛋白和脑部小血管疾病都不是很好。 理解，尤其是在人类身上。这主要归因于体内评估技术的缺乏。 BBB功能。PI是微血管功能的非侵入性成像领域的领先专家，他的实验室 最近开发、优化和验证了一种核磁共振技术来评估血脑屏障对水的渗透性 分子。我们使用这种新技术的初步研究已经显示出强有力的证据表明：1)显著 轻度认知障碍(MCI)患者的血脑屏障破坏可通过非增强MRI检测到；2) 血脑屏障破坏的程度与淀粉样蛋白负荷有关；3)血脑屏障功能可以预测认知 功能，特别是在内存域中。 因此，本应用程序的中心目标是利用这些技术进步，并将 血脑屏障在MCI和早期痴呆中的分解及其与AD和Small的因果关系 血管病理学。血脑屏障对三种不同大小的分子，特别是水(相对分子质量)的渗透性 18g/mol)、Gd磁共振造影剂(相对分子质量547g/mol)和白蛋白(相对分子质量66K G/mol)将在相同的受试者身上进行测量。人类患者研究将与动物研究平行进行 模型，以便临床上相关的发现可以在实验模型中得到验证。炎症的作用 在BBB中，还将检查细目。这些关系将在横断面和 纵向方式。这个多模式、多学科的项目有三个目标。目标1将研究 血脑屏障破坏、淀粉样蛋白、tau病理、小血管病理和 125名老年参与者中的炎症标志物，包括认知正常者、轻度认知障碍和早期痴呆。这个 这些变量之间的相互关系将在一个机械模型的框架内进行研究。目标2将 对这些参与者进行30个月的随访，并调查血脑屏障与血脑屏障之间的纵向关系 阿尔茨海默病病理、小血管病理、炎症标志物和认知的分解和进展 功能。最后，在目标3中，我们将验证ADRD患者血脑屏障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个新的啮齿动物模型。 这些相对纯病理的啮齿动物模型有望揭示更明确的关系。 血脑屏障破坏与AD和小血管病理之间的关系。