Integrin regulation of vascular function in Alzheimer's disease

整合素对阿尔茨海默病血管功能的调节

• 批准号: 10901016
• 负责人: Antoine Louveau
• 金额: $ 60.55万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901016
• 关键词: Address; Age Months; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Behavioral; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Blood flow; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebral small vessel disease; Cerebrovascular system; Chemicals; Cognition; Cognitive; Collagen; Data; Dementia; Development; Disease; Early Onset Alzheimer Disease; Electron Microscopy; Endothelial Cells; Endothelium; Excision; Extravasation; Fibrinogen; Functional disorder; Genetic; Goals; Histology; Impaired cognition; In Vitro; Infiltration; Inflammation; Integrin Binding; Integrins; Intrathecal Injections; Knowledge; Late Onset Alzheimer Disease; Mediating; Methods; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathology; Pathway interactions; Patients; Pericytes; Pre-Clinical Model; Preventive; Proteins; Regulation; Research; Risk Factors; Role; Signal Transduction; TGFB1 gene; Testing; Therapeutic; Transforming Growth Factors; Up-Regulation; Vascular Diseases; abeta accumulation; amyloid pathology; blood-brain barrier function; blood-brain barrier permeabilization; brain endothelial cell; brain parenchyma; cognitive function; cytokine; genome wide association study; glial activation; glymphatic function; glymphatic system; hyperphosphorylated tau; improved; in vivo; inhibitor; mouse model; neuroinflammation; neurovascular; novel therapeutics; overexpression; pharmacologic; social; tau Proteins; transcriptomics; β-amyloid burden

PROJECT SUMMARY/ABSTRACT This project aims at understanding the molecular mechanisms governing vascular and blood brain barrier function in Alzheimer’s disease (AD), and their involvement in AD pathophysiology. AD research has recently identified vascular dysfunction as a central hallmark of the disease correlating with cognitive impairment, and actively mediating the neuroinflammatory and amyloid burden in pre-clinical models and patients. However, the molecular mechanisms regulating vascular disfunction in AD remains limited. We found that the integrin CD49a, highly expressed in endothelial cells and pericytes and induced by the transforming growth factor TGF, is associated with AD (genome wide associated studies) and that modulation of CD49a expression impact the pathophysiology of AD in a pre-clinical model. We therefore hypothesize that CD49a expression by blood endothelial cells regulates vascular function in AD, mediates the deleterious effects of TGFb on vascular amyloidosis and negatively contribute to AD pathophysiology and cognition. Guided by our preliminary data, we propose to address our hypothesis using the following aims: Aim1: Determine how CD49a regulates blood brain barrier function. Aim2: Test the relationship between TGFb and CD49a in endothelial cells. Aim 3: Test the contribution of endothelial CD49a in the pathophysiology of Alzheimer’s disease. Collectively, our proposed studies will have a broad impact by: a) decipher the cell specific role of CD49a in blood brain barrier function; b) identify CD49a has a downstream pathway for the deleterious effects of TGFb on vascular pathology in AD; c) assert the role of CD49a and vascular dysfunction in the pathophysiology of AD, and d) highlight the therapeutic potential of targeting CD49a in AD and other neurovascular disorders.

项目总结/摘要 该项目旨在了解血管和血脑的分子机制 阿尔茨海默病（AD）中的屏障功能，以及它们在AD病理生理学中的参与。AD研究 最近确定血管功能障碍是与认知功能相关的疾病的中心标志， 损伤，并在临床前模型中积极介导神经炎症和淀粉样蛋白负荷， 患者然而，调节AD血管功能障碍的分子机制仍然有限。我们发现 整合素CD 49 a在内皮细胞和周细胞中高表达，并由转化的 生长因子TGF β 1与AD相关（全基因组相关研究）和CD 49 α的调节 表达影响临床前模型中AD的病理生理学。因此，我们假设CD 49 a 血管内皮细胞的表达调节AD的血管功能，介导 TGF β在血管淀粉样变性中起重要作用，并对AD的病理生理和认知产生负面影响。 根据我们的初步数据，我们建议使用以下目标来解决我们的假设： 目的1：确定CD 49 a如何调节血脑屏障功能。 目的2：检测内皮细胞中TGF β和CD 49 a的关系。 目的3：检测内皮细胞CD 49 a在阿尔茨海默病病理生理中的作用。 总的来说，我们提出的研究将通过以下方式产生广泛的影响：a）破译细胞特异性作用， CD 49 a在血脑屏障功能中的作用; B）鉴定CD 49 a是否具有下游通路的有害作用 c）肯定CD 49 a和血管功能障碍在AD中的作用， d）突出了在AD和其他疾病中靶向CD 49 α的治疗潜力， 神经血管疾病