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