The blood-brain barrier and Alzheimer pathology

血脑屏障和阿尔茨海默病病理学

• 批准号: 10800246
• 负责人: William J. Jagust
• 金额: $ 66.25万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10800246
• 关键词: Age-associated memory impairment; Aging; Albumins; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Area; Astrocytes; Biological; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Characteristics; Cognitive; Contrast Media; Data; Deposition; Development; Discipline of Nuclear Medicine; Disease; Elderly; Episodic memory; Etiology; Event; Extravasation; Feedback; Genetic; Hippocampus; Histopathology; Human; Human Volunteers; Immunohistochemistry; Impaired cognition; Impairment; Individual; Inflammatory Response; Infusion procedures; Intervention; Intuition; Link; Magnetic Resonance Imaging; Maps; Measurement; Measures; Medial; Mediating; Memory; Modeling; Molecular; Mus; Neurologic; Neuronal Dysfunction; Neurophysiology - biologic function; Pathogenesis; Pathologic; Pathology; Pathway interactions; Penetration; Persons; Plasma Proteins; Positron-Emission Tomography; Process; Proteins; Rodent; Scanning; Serum Albumin; Serum Proteins; Signal Transduction; Social Problems; Temporal Lobe; Testing; Thick; Thinness; Time; Transforming Growth Factor beta; Transgenic Mice; Translating; Vascular Diseases; aged; aging brain; blood-brain barrier disruption; blood-brain barrier function; blood-brain barrier permeabilization; cerebrovascular; cognitive change; cognitive function; contrast enhanced; effective therapy; human data; imaging approach; improved; loss of function; mild cognitive impairment; molecular marker; molecular size; mouse model; neural; novel; pharmacologic; pre-clinical; protein aggregation; regional difference; tau Proteins; tau aggregation; tau mutation; temporal measurement; theories; translational model; transmission process

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.

项目摘要 血管血脑屏障（BBB）功能障碍和脑血管漏 存在于衰老过程中和阿尔茨海默病 (AD) 中，并且与以下疾病的发生有关： 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学途径 BBB 功能障碍后。虽然直觉上认为基本血管功能丧失 保护大脑的接口预计会引起神经系统并发症， 可能会导致AD，之前还没有明确定义的机制连接BBB AD 病理功能障碍。人类的现有数据受到与可能的相关的限制 BBB 渗漏的区域差异和 BBB 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、-淀粉样蛋白 (A) 和 tau 蛋白的病理聚集体。 很少有研究探讨这些病理蛋白与 BBB 的关系 破坏，并且没有探索四种截然不同的情况：（1）没有 BBB破坏导致的AD病理蛋白与BBB破坏的关系（二） 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 破坏。 (4)AD蛋白病理与BBB破坏形成正反馈 源自任一者的循环，并通过传播/传播的加剧而相关 BBB 破坏造成的蛋白质病理。 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 使用 PET 扫描获得 tau 和 A 测量值以及动态对比度增强 磁共振成像 (DCE-MRI) 以获得 BBB 测量值，研究 AD 转基因小鼠模型，我们将在其中操纵 BBB。这些研究将共同 在小鼠模型中探索 AD 发病机制，从而能够解剖个体 通过单独操作，BBB 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状况的观察的研究 临床前AD。