Vascular MicroRNA-212 in CAA and Alzheimer's disease

总结 脑血管的病理变化导致阿尔茨海默病（AD）和AD相关性痴呆 （ADRD）.β淀粉样蛋白（Aβ）介导的内皮损伤可能导致微出血、中风、缺氧、 脑血流和整个神经血管单元的功能障碍，导致认知障碍。微型 RNA（miRNAs）调节基因表达和蛋白质水平，具有细胞存活和增殖所必需的功能。 在正常和压力条件下运作。miRNAs在大脑中高度富集，并在大脑中发挥关键作用。 发展和疾病。虽然血管对AD病理学的贡献是公认的，但 AD/ADRD脑中内皮细胞中的miRNA表达仍然大部分未被探索。 我们建议评估淀粉样蛋白攻击对脑内皮细胞中miRNA调控的影响， 阐述了Aβ肽（一种已知的AD致病因子）触发内皮细胞凋亡的总体假设， miRNA改变，最显著的是miR-212下调，有助于血脑屏障 (BBB)衰竭和AD特征性的神经血管功能障碍。我们的具体目标是展示 假设Aβ肽通过内皮细胞促进脑血管功能障碍和BBB衰竭， miR-212。 使用人原代和永生化内皮细胞，从转基因小鼠纯化脑血管， 血管性淀粉样变性和来自具有血管性Aβ和纯A β的人类AD病例的死后脑血管 脑淀粉样血管病（CAA）病例，我们旨在验证以下假设：目的1：毒性Aβ物质 特异性降低脑内皮细胞中的miR-212。目的2：MiR-212靶点调节内皮细胞 细胞应激/死亡基因和途径。目的3：miR-212缺失破坏BBB功能。 该项目将受益于两名分别专门从事以下工作的专业人员的综合专业知识和合作： CAA和AD中的血管/内皮功能障碍以及AD和ADRD中的miRNA研究。这项研究将使我们 为了阐明特定血管miRNAs的作用，并通过重新建立它们的正确平衡， 表达和脑血管系统中的生物网络。拟议研究的长期目标将 开发针对AD神经血管功能障碍的新型miRNA治疗策略， 相关的痴呆症

Summary Pathological changes in the brain vasculature contribute to Alzheimer’s disease (AD) and AD-related dementias (ADRD). Amyloid β (Aβ)-mediated endothelial damage may lead to microbleeds, stroke, hypoxia, alterations in cerebral blood flow and malfunction of the entire neurovascular unit, contributing to cognitive impairment. Micro- RNAs (miRNAs) regulate gene expression and protein levels, bearing functions essential for cell survival and functioning in normal and stress conditions. MiRNAs are highly enriched in the brain and play critical roles in development and disease. While the vascular contributions to AD pathology are well recognized, the changes in miRNA expression in endothelial cells in the AD/ADRD brain are still mostly unexplored. We propose to assess the effect of amyloid challenge on miRNA regulation in cerebral endothelial cells, addressing the overarching hypothesis that the Aβ peptide, a known causative factor of AD, triggers endothelial miRNA alterations, the most significant being miR-212 downregulation, contributing to the blood-brain barrier (BBB) failure and neurovascular dysfunction characteristic of AD. Our specific goal is to demonstrate the hypothesis that the Aβ peptide promotes cerebrovascular dysfunction and BBB failure via endothelial miR-212. Using human primary and immortalized endothelial cells, purified cerebral vessels from transgenic mice with vascular amyloidosis, and post-mortem brain vasculature from human AD cases with vascular Aβ and pure cerebral amyloid angiopathy (CAA) cases, we aim to test the following hypotheses that: Aim 1: toxic Aβ species specifically reduce miR-212 in cerebral endothelial cells. Aim 2: MiR-212 targets modulate endothelial cell stress/death genes and pathways. Aim 3: miR-212 loss disrupts BBB function. This project will benefit from the combined expertise and collaboration of two PIs specialized respectively in vascular/endothelial dysfunction in CAA and AD and miRNA research in AD and ADRD. This study will allow us to clarify the role of specific vascular miRNAs and, by re-establishing their correct equilibrium, restore gene expression and biological networks in the cerebral vasculature. The long-term goal of the proposed research will be the development of novel miRNA-focused therapeutic strategies against neurovascular dysfunction in AD and related dementias.