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）和脑血管渗漏的功能障碍是 在衰老和阿尔茨海默氏病（AD）中存在，并与 临床前温和认知障碍。根据最近的发现，我们定义了一个高度的 直接引起神经功能障碍和认知障碍的剥夺生物学途径 遵循BBB功能障碍。虽然直观的是基本血管的功能丧失 预计保护大脑的界面会引起神经系统并发症 可能有助于AD，以前没有连接BBB的明确定义的机制 广告病理功能障碍。人类的现有数据遭受与可能的限制 BBB泄漏的区域差异和BBB破坏的临时特征 特别是关于与AD有关的两种蛋白质的沉积 tau的发病机理，淀粉样蛋白（A）和病理聚集体。 很少有研究检查这些病理蛋白与BBB的关系 破坏，并且没有对四种完全不同的情况进行探索：（1）没有 AD病理蛋白与BBB破坏之间的关系（2）BBB破坏引导 增加这些蛋白质或（3）增加这些蛋白的积累的积累 导致BBB破坏。 （4）AD蛋白质病理和BBB破坏形成积极的反馈 循环源于两者，并且通过加剧的传播/传播而相关 由BBB破坏产生的条件受到的蛋白质病理。 在这项研究中，我们将在认知正常人中结合描述性纵向数据 使用PET扫描获得TAU和A测量和动态对比度增强 通过研究 AD的转基因小鼠模型，我们将操纵BBB。这些研究将共同 小鼠模型中AD发病机理的探针机制，使个人能够解剖 BBB破坏，淀粉样蛋白和TAU的贡献是通过分别操纵和人类的 将这些基本发现转化为人类衰老状况的研究 临床前广告。