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.

抽象的散发性脑淀粉样血管病（CAA）是一种由脑血管沉积引起的小血管疾病 CAA 经常与阿尔茨海默病 (AD) 重叠，可能是因为 Aβ 是重要的是，没有针对疾病的治疗方法。与该项目相关的 CAA 发病机制的分子机制。 CAA 尚未被完全了解，从而限制了我们阻止这种情况发生和发展的能力尽管 CAA 和血管性脑损伤之间存在机制差异。 AD 中的神经退行性损伤，临床上 CAA 与 AD 重叠，并且与更严重的 AD 相关该应用程序旨在推进 AD 患者认知障碍的早期阶段的概念。 CAA，内皮源性Aβ在脑血管壁沉积是重要机制我们对培养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）用于确定。人类和小鼠脑血管内皮的整体基因表达谱。并使用 CAA 小鼠实验模型来验证和扩展在培养中获得的观察结果我们鉴定了以前未被识别的（Aβ 独立的）β 位点的内皮功能。淀粉样前体蛋白（APP）-裂解酶（BACE1）与其同源物（BACE2）之间的一致性。人类和小鼠内皮细胞的研究结果与 BACE1 的强烈进化保守性一致然而，内皮 BACE1 发挥疼痛血管作用，而内皮 BACE2 则发挥作用。似乎是以前未被认识的且非常重要的血管保护分子。分析脆弱小鼠内皮细胞中 BACE1 和 BACE2 的功能和信号转导 CAA 认为，内皮细胞中功能失调的 BACE1 和 BACE2 会促进 Aβ 沉积升高基于这些初步发现，我们的工作假设是内皮 BACE1。我们预计 BACE2 在脑血管稳态和 CAA 发病机制中发挥着独特的作用。该项目的成功完成将为利用内皮BACE1和BACE2作为药物提供新的机会治疗干预的分子靶标，旨在防止 CAA 对患者的不利影响脑血管和认知功能。