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Role of endothelium in pathogenesis of cerebral amyloid angiopathy

内皮在脑淀粉样血管病发病机制中的作用

基本信息

批准号：
10624872
负责人：
Zvonimir S Katusic
金额：
$ 64.8万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624872
关键词：
Abeta clearance Abeta synthesis Age-associated memory impairment Agreement Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloidosis Arteries Bioinformatics Blood Vessels Brain Brain Injuries Cell Separation Cerebral Amyloid Angiopathy Cerebral hemisphere hemorrhage Cerebrovascular Physiology Cerebrovascular system Clinical Dementia Deposition Development Disease Disease Progression Elderly Endothelial Cells Endothelium Enzymes Experimental Models Fluorescence-Activated Cell Sorting Genes Homeostasis Homologous Gene Human Impaired cognition Impairment In Vitro Injury Intercellular Fluid Knockout Mice Link Microvascular Dysfunction Molecular Mus Nerve Degeneration Pathogenesis Pathway interactions Patients Persons Pharmaceutical Preparations Play Prevention Production Proteins Regulation Reporting Risk Role Signal Transduction Site Sporadic Cerebral Amyloid Angiopathy abeta accumulation abeta deposition aging brain alpha secretase beta-site APP cleaving enzyme 1 brain endothelial cell brain parenchyma cerebral microvasculature cerebrovascular cerebrovascular pathology cognitive function design experimental study molecular targeted therapies mouse model next generation next generation sequencing preservation prevent therapeutic development therapeutic target therapy design transcriptome transcriptome sequencing

项目摘要

ABSTRACT Sporadic cerebral amyloid angiopathy (CAA) is a small vessel disease caused by cerebrovascular deposition of amyloid-β (Aβ). CAA frequently overlaps with Alzheimer’s disease (AD), presumably because Aβ is considered major culprit in development of AD pathology. Importantly, there is no disease-specific treatment available to patients with CAA. Relevant to this project, molecular mechanisms underlying pathogenesis of CAA are incompletely understood thereby limiting our ability to prevent initiation and progression of this disease. Despite mechanistic differences between vascular-induced brain injury in CAA and neurodegenerative injury in AD, clinically, CAA overlaps with AD and it is associated with more severe cognitive impairment in AD patients. This application is designed to advance the concept that in early stages of CAA, deposition of endothelium-derived Aβ in cerebral blood vessel wall is an important mechanism contributing to pathogenesis of the disease. We performed extensive preliminary studies on cultured human brain microvascular endothelial cells (BMECs), mouse microvessels, and brain endothelial cells isolated by fluorescence activated cell sorting (FACS). Next generation sequencing (RNA-Seq) was used to determine global gene expression profiles in human and murine cerebrovascular endothelium. Genetically modified mice and a murine experimental model of CAA were used to validate and expand observations obtained in cultured human endothelium. We identified previously unrecognized (Aβ-independent) endothelial functions of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) and its homologue (BACE2). Consistency between findings in human and murine endothelium was in agreement with strong evolutionary conservation of BACE1 and BACE2. However, while endothelial BACE1 exerts detrimental vascular effects, endothelial BACE2 appears to be previously unrecognized and very important vascular protective molecule. Further preliminary analyses of BACE1 and BACE2 function and signaling in endothelium of mice vulnerable to development of CAA, suggested that dysfunctional BACE1 and BACE2 in endothelium promote elevated Aβ deposition in the cerebral blood vessels. Based on these preliminary findings our working hypothesis is that endothelial BACE1 and BACE2 play distinct roles in cerebrovascular homeostasis and pathogenesis of CAA. We anticipate that successful completion of this project will offer new opportunities to utilize endothelial BACE1 and BACE2 as molecular targets for therapeutic interventions designed to prevent detrimental effects of CAA on cerebrovascular and cognitive function.

摘要