Human vascular model to study Alzheimer's Disease

描述（由申请人提供）：血管疾病和心血管危险因素（糖尿病、高脂血症和高血压）与阿尔茨海默病（AD）密切相关，但它们导致AD的机制尚不清楚。血管功能障碍导致脑灌注不足和血脑屏障功能受损，在阿尔茨海默病早期发生，并在早期病理生理中起核心作用。阿尔茨海默病研究的关键障碍包括缺乏对心血管危险因素如何导致阿尔茨海默病或调节asas损伤的了解，以及缺乏研究阿尔茨海默病早期血管疾病的人体组织模型。我们的初步数据表明，通过快速解剖从器官供体中分离出的离体小动脉来研究asas和心血管危险因素对微血管的反应是可行的。我们的总体目标是确定asas诱导微血管损伤的关键机制，并系统研究心血管危险因素如何调节asas对内皮功能、氧化应激和血管炎症的影响。研究人员推测，乙酰胆酸通过氧化应激、晚期糖基化终产物受体（RAGE）和核因子κ B （NF-KB）信号的激活诱导内皮功能障碍和血管炎症，高血糖症（HG）和棕榈酸（PA）会通过调节大脑和外周脂肪小动脉中的这些途径加重乙酰胆酸的血管毒性。在Aim 1中，我们将量化暴露于asg±HG或PA)对AD、轻度认知障碍（MCI）和认知正常（CN）受试者的小脑膜动脉血管功能的影响，同时确定调节这些反应的关键炎症和氧化应激信号机制。在Aim 2中，我们将通过比较暴露于asg±HG或PA的尸体和活体脂肪小动脉的血管、氧化应激和炎症信号反应，来建立外周脂肪小动脉作为一个实用的人类替代模型的有效性，以研究大脑中央小动脉对AD应激源的反应。该建议将为关键的相互作用和调制效应提供新的机制见解

DESCRIPTION (provided by applicant): Vascular disease and cardiovascular risk factors (diabetes, hyperlipidemia and hypertension) are strongly associated with Alzheimer's disease (AD) yet the mechanisms by which they lead to AD remain unknown. It is now well-recognized that vascular dysfunction leading to cerebral hypo perfusion and impaired blood brain barrier function occur early in AD and has a central role in early pathophysiology. Critical obstacles in AD research include the lack of knowledge of how cardiovascular risk factors contribute to AD or modulate Aß injury, and the lack of a human tissue model to study early vascular disease in AD. Our preliminary data show the feasibility of using ex-vivo leptomeningeal arterioles isolated by rapid autopsy from organ donors to study micro vascular response to Aß and cardiovascular risk factors. Our overall goal is to identify key mechanisms underlying Aß -induced micro vascular injury and systematically study how cardiovascular risk factors modulate Aß effects on endothelial function, oxidative stress and vascular inflammation. We hypothesize that Aß induces endothelial dysfunction and vascular inflammation through oxidative stress and activation of receptor for advanced glycation end products (RAGE) and nuclear factor kappa B (NF-KB) signaling, and hyperglycemia (HG) and palmitic acid (PA) will exacerbate Aß vascular toxicity by modulating these pathways in cerebral and peripheral adipose arterioles. In Aim 1 we will quantify the effects of exposure to Aß ± HG or PA) on vascular function of leptomeningeal arterioles taken from AD, mild cognitive impairment (MCI) and cognitively normal (CN) subjects while identifying key inflammatory and oxidative stress signaling mechanisms modulating the responses. In Aim 2 we will establish the validity of peripheral adipose arterioles as a practical human surrogate model to study central brain arteriole response to AD stressors by comparing vascular, oxidative stress and inflammatory signaling responses in cadaver and living subject adipose arterioles exposed to Aß ± HG or PA to cadaver leptomeningeal arterioles. The proposal will provide novel mechanistic insights on the critical interaction and modulating effects of cardiovascular risk factors and Aß on human micro vessels while comparing vascular responses to known AD stressors among AD, MCI and CN subjects. The validation of adipose arterioles as an acceptable surrogate to brain micro vessels will provide a practical human model to study mechanisms and treatments of early vascular injury from AD stressors.