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：
10311153
负责人：
Zvonimir S Katusic
金额：
$ 65.45万
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/10311153
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 Cleaved cell 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 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.

抽象的零星脑淀粉样血管病（CAA）是由脑血管沉积引起的小血管疾病淀粉样蛋白-β（Aβ）的CAA经常与阿尔茨海默氏病重叠（AD），大概是因为Aβ是被认为是AD病理发展的主要罪魁祸首。重要的是，没有特定疾病的治疗可用于CAA患者。与该项目相关的是，分子机制 CAA未完全理解，从而限制了我们防止启动和进步的能力疾病。尽管CAA中血管引起的脑损伤之间存在机械差异，并且 AD的神经退行性损伤在临床上，CAA与AD重叠，并且与更严重的 AD患者的认知障碍。该应用程序旨在推进以下概念 CAA，内皮衍生的Aβ在脑血管壁中的沉积是重要的机制有助于疾病的发病机理。我们对培养的人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由荧光激活的细胞分选（FACS）。下一代测序（RNA-Seq）用于确定人和鼠脑脑血管森林中的全球基因表达谱。转基因小鼠并使用CAA的鼠实验模型来验证和扩大在培养的中获得的观察结果人内皮。我们确定了先前未识别的（非Aβ独立的）β位点的内皮功能淀粉样前体蛋白（APP） - 分解酶（BACE1）及其同源物（BACE2）。之间的一致性人类和鼠内皮中的发现与BACE的强烈进化保护一致和Bace2。但是，虽然内皮BACE1执行有害的血管作用，但内皮BACE22 似乎以前未被认可且非常重要的血管保护分子。进一步的初步 BACE1和BACE2功能的分析以及小鼠内皮的信号传导，这些小鼠容易受到发展的影响 CAA表明，内皮中功能失调的BACE1和BACE2促进了Aβ的升高脑血管。基于这些初步发现，我们的工作假设是内皮Bace1 BACE2在脑血管稳态和CAA发病机理中起着不同的作用。我们预料到这一点该项目的成功完成将为使用内皮BACE1和BACE2的新机会作为用于预防CAA有害影响的热干预措施的分子靶标脑血管和认知功能。