Mechanisms of cerebrovascular barrier dysfunction caused by APP and PSEN1 mutations and amyloid beta exposure

APP和PSEN1突变及β淀粉样蛋白暴露引起脑血管屏障功能障碍的机制

• 批准号: 10401690
• 负责人: Peter C Searson
• 金额: $ 21.78万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401690
• 关键词: Address; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Atrophic; Biological; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; Cell Differentiation process; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Cognitive deficits; DNA Sequence Alteration; Disease; Disease Progression; Environmental Risk Factor; Epidemiology; Etiology; Functional disorder; Gene Expression; Generations; Genes; Genetic; Human; Hybrids; Image; Immunohistochemistry; Impaired cognition; Inflammation; Intervention; Intrinsic factor; Laboratories; Libraries; Measurement; Memory Loss; Microvascular Dysfunction; Modeling; Mutation; Neurofibrillary Tangles; Pathway interactions; Pharmacology; Process; Reactive Oxygen Species; Research; Risk; Senile Plaques; Sleep; Smooth Muscle Myocytes; Symptoms; Tissue Engineering; Tissue-Specific Gene Expression; Transgenic Mice; Vascular Diseases; abeta deposition; age related; amyloid formation; arteriole; base; blood-brain barrier function; brain endothelial cell; cell type; cerebrovascular; cerebrovascular pathology; diet and exercise; glucose transport; imaging study; induced pluripotent stem cell; lifestyle factors; mutational status; neuroimaging; next generation; presenilin-1; stem cell technology

Project Summary The causes of Alzheimer’s disease (AD) are thought to include a combination of age-related changes in the brain, genetic factors (risk and deterministic genes), and environmental and lifestyle factors (e.g. diet, exercise, sleep). Age-related changes in the brain include atrophy, inflammation, generation of reactive oxygen species, and vascular dysfunction. A central question in AD research is whether vascular dysfunction (specifically in small vessels in the brain) is a primary cause of AD etiologies (vascular hypothesis) or a secondary consequence of other processes (e.g. amyloid cascade hypothesis). Studies in humans and transgenic mice have established that blood-brain barrier (BBB) dysfunction can occur prior to amyloid beta deposition, cerebral amyloid angiopathy (CAA), and the onset of cognitive impairment. The onset of AD is thought to occur 20 years or more before symptoms such as memory loss and cognitive deficits. While this window provides opportunities for intervention, it also poses challenges in uncovering the underlying causes of the disease. Identifying the mechanisms of BBB dysfunction is crucial to understanding disease progression and identifying targets for intervention. The objective of this supplement project is to identify the mechanisms of BBB dysfunction occurring within a tissue-engineered brain arteriole model caused by APP and PSEN1 mutations, and by amyloid beta (Aβ) exposure. The objective will be addressed in two aims. In Aim 1 brain microvascular endothelial cells (iBMECs) and smooth muscle cells (iSMCs) differentiated from an isogenic panel of iPSCs harboring PSEN1(M146V) or APP(Swe) mutations, along with wild type controls, will be incorporated into a brain-specific arteriole model developed in our laboratory. From analysis of the differential gene expression profiles of iBMECs and iSMCs, biological pathways altered by AD mutations and Aβ exposure that may underlie cerebrovascular dysfunction will be identified. In Aim 2 a selected library of functional assays will be used to determine mutation-dependent and amyloid beta-dependent mechanisms of cerebrovascular dysfunction. Functional measurements will include a core assays associated with barrier function, as well as assays developed based on pathways identified in Aim 1. This hybrid approach will enable us to focus on cerebrovascular functions that are most likely to be altered by mutational status and Aβ exposure.

项目概要 阿尔茨海默病 (AD) 的病因被认为包括与年龄相关的大脑功能变化的综合作用。 大脑、遗传因素（风险和决定性基因）以及环境和生活方式因素（例如饮食、运动、 睡眠）与年龄相关的大脑变化包括萎缩、炎症、活性氧的产生、 AD 研究的一个中心问题是是否存在血管功能障碍（特别是在 大脑中的小血管）是 AD 病因（血管假说）的主要原因，还是次要原因 其他过程的后果（例如淀粉样蛋白级联假说）。 已经确定血脑屏障（BBB）功能障碍可能在β淀粉样蛋白沉积之前发生， 脑淀粉样血管病 (CAA) 和认知障碍的发生 人们认为 AD 的发生。 20 年或更长时间，出现记忆丧失和认知缺陷等症状。 它为干预提供了机会，但也为揭示疾病的根本原因带来了挑战。 确定 BBB 功能障碍的机制对于了解疾病进展和识别 BBB 功能至关重要 干预的目标。 该补充项目的目标是确定 BBB 功能障碍发生的机制 由 APP 和 PSEN1 突变以及β淀粉样蛋白 (Aβ) 引起的组织工程脑动脉模型 目标将在两个目标中得到解决：1.脑微血管内皮细胞。 (iBMEC) 和平滑肌细胞 (iSMC) 从含有 iPSC 的同基因组中分化而来 PSEN1(M146V) 或 APP(Swe) 突变以及野生型对照将被纳入大脑特异性 我们实验室开发的小动脉模型来自对差异基因表达谱的分析。 iBMEC 和 iSMC、AD 突变和 Aβ 暴露改变的生物途径可能是其背后的原因 在目标 2 中，将使用选定的功能分析库来识别脑血管功能障碍。 确定脑血管功能障碍的突变依赖性和淀粉样蛋白β依赖性机制。 功能测量将包括与屏障功能相关的核心检测以及检测 根据目标 1 中确定的途径开发。这种混合方法将使我们能够专注于 脑血管功能最有可能因突变状态和 Aβ 暴露而改变。