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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：
10478114
负责人：
Zvonimir S Katusic
金额：
$ 65.41万
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/10478114
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 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 amyloid precursor protein processing base 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.

摘要散发性脑淀粉样血管病是一种脑血管沉积引起的小血管疾病 β淀粉样蛋白（Aβ）。CAA经常与阿尔茨海默病（AD）重叠，可能是因为Aβ是被认为是AD病理学发展的罪魁祸首。重要的是，没有针对特定疾病的治疗方法可用于CAA患者。与本项目相关的是， CAA是不完全理解，从而限制了我们的能力，以防止启动和进展，这疾病尽管CAA中血管诱导的脑损伤与在临床上，CAA与AD重叠，并且与更严重的AD相关。 AD患者的认知障碍。此应用程序旨在推进概念，在早期阶段，脑血管壁内皮源性Aβ沉积是CAA的重要机制有助于疾病的发病机制。我们对培养的人类进行了广泛的初步研究，脑微血管内皮细胞（BMEC）、小鼠微血管和脑内皮细胞，荧光激活细胞分选（FACS）。使用下一代测序（RNA-Seq）来确定人类和小鼠脑血管内皮细胞的整体基因表达谱。遗传修饰的小鼠和CAA的小鼠实验模型用于验证和扩展在培养的人内皮细胞。我们鉴定了以前未被认识的（Aβ非依赖性）β位点的内皮功能，淀粉样前体蛋白（APP）裂解酶（BACE 1）及其同源物（BACE 2）。之间的一致性在人类和小鼠内皮中的发现与BACE 1的强进化保守性一致 BACE 2然而，虽然内皮BACE 1发挥有害的血管作用，内皮BACE 2 似乎是以前未被认识的和非常重要的血管保护分子。进一步的初步 BACE 1和BACE 2功能和信号转导在易受发展的小鼠内皮中的分析 CAA，提示内皮细胞中BACE 1和BACE 2的功能障碍促进了Aβ沉积的增加，脑血管基于这些初步发现，我们的工作假设是内皮BACE 1 BACE 2在脑血管内环境稳定和CAA发病中起着不同的作用。我们预计该项目的成功完成将提供利用内皮BACE 1和BACE 2作为分子靶点的治疗干预，旨在防止CAA的有害影响，脑血管和认知功能。