Vascular MicroRNA-212 in CAA and Alzheimer's disease

CAA 和阿尔茨海默病中的血管 MicroRNA-212

• 批准号: 10807420
• 负责人: Silvia Fossati
• 金额: $ 39.39万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10807420
• 关键词: AD transgenic mice; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloidosis; Autopsy; Binding Sites; Biological; Biological Assay; Biological Models; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Budgets; Candidate Disease Gene; Caspase; Cell Death; Cell Survival; Cell physiology; Cells; Cellular Stress; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Cessation of life; Characteristics; Co-Immunoprecipitations; Collaborations; Data; Deposition; Development; Diagnostic; Disease; Disease Progression; Down-Regulation; Elderly; Electrical Resistance; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Equilibrium; Essential Genes; Exhibits; Failure; Functional disorder; Funding; Gatekeeping; Gene Expression; Gene Proteins; Genes; Goals; Grant; Hemorrhage; Homologous Gene; Human; Hypoxia; Image; Immunohistochemistry; Impaired cognition; In Situ; In Situ Hybridization; In Vitro; Ischemia; Measures; Mediating; Mediator; Methods; MicroRNAs; Modeling; Mus; Mutagenesis; Neurodegenerative Disorders; Neurons; Northern Blotting; Oligonucleotides; Pathogenesis; Pathologic; Pathology; Pathway interactions; Permeability; Phenotype; Physiological; Play; Preparation; Proteins; Quantitative Reverse Transcriptase PCR; Regulation; Regulator Genes; Reporter; Research; Research Personnel; Risk; Role; Secure; Severity of illness; Site; Small RNA; Stress; Stroke; System; TNFRSF10A gene; TNFRSF10B gene; Testing; Tg2576; Therapeutic; Toxic effect; Transgenic Mice; United States National Institutes of Health; Untranslated RNA; Variant; Western Blotting; Work; abeta deposition; abeta toxicity; beta amyloid pathology; blood-brain barrier disruption; blood-brain barrier function; blood-brain barrier permeabilization; brain endothelial cell; cell injury; cerebrovascular; clinically relevant; endothelial dysfunction; experimental study; gene network; improved; in vivo; mRNA sequencing; monolayer; mouse model; neurovascular; neurovascular unit; novel; overexpression; response; therapeutic miRNA; therapeutically effective; translational study; vascular cognitive impairment and dementia; vascular contributions

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.

摘要 脑血管病变导致阿尔茨海默病(AD)和AD相关痴呆 (ADRD)。淀粉样蛋白β(Aβ)介导的内皮损伤可导致微出血、中风、缺氧、血管内皮细胞病变 整个神经血管单位的脑血流和功能障碍，导致认知障碍。微型机 RNAs(MiRNAs)调节基因表达和蛋白质水平，承担细胞生存和 在正常和紧张的条件下工作。MiRNAs在大脑中高度丰富，并在 发展和疾病。虽然血管在AD病理中的作用得到了很好的认识，但血管在 在AD/ADRD脑内皮细胞中miRNA的表达大多尚不清楚。 我们建议评估淀粉样蛋白攻击对脑内皮细胞miRNA调节的影响。 解决一个重要的假设，即已知的AD致病因素Aβ肽触发内皮细胞 MiRNA改变，最显著的是miR-212下调，导致血脑屏障 (BBB)衰竭和神经血管功能障碍是阿尔茨海默病的特征。我们的具体目标是展示 Aβ肽通过内皮促进脑血管功能障碍和血脑屏障衰竭的假说 MIR-212。 使用人原代和永生化内皮细胞，从转基因小鼠中纯化脑血管 血管Aβ和单纯AD患者的血管淀粉样变性和死后脑血管形成 脑淀粉样血管病的病例，我们的目的是检验以下假设：目的1：毒性Aβ物种 特异性降低脑血管内皮细胞miR-212的表达。目的2：MIR-212靶点调控内皮细胞 细胞应激/死亡基因和途径。目的3：MIR-212的丢失扰乱了血脑屏障功能。 该项目将受益于两个专业人员的综合专业知识和协作 CAA和AD的血管/内皮功能障碍以及AD和ADRD的miRNA研究。这项研究将使我们能够 阐明特定的血管miRNAs的作用，并通过重新建立其正确的平衡，恢复基因 脑血管系统中的表达和生物网络。拟议研究的长期目标将是 开发以miRNA为核心的治疗AD和AD的神经血管功能障碍的新策略 相关痴呆症。