Human vascular model to study Alzheimer's Disease

描述（由申请人提供）：血管疾病和心血管风险因素（糖尿病、高脂血症和高血压）与阿尔茨海默病（AD）密切相关，但导致AD的机制仍不清楚。目前公认的是，血管功能障碍导致脑灌注不足和血脑屏障功能受损发生在AD的早期，并在早期病理生理学中具有核心作用。AD研究中的关键障碍包括缺乏对心血管危险因素如何导致AD或调节血管损伤的知识，以及缺乏研究AD早期血管疾病的人体组织模型。我们的初步数据表明，使用离体软脑膜小动脉的可行性，从器官捐献者的快速尸检分离，研究微血管反应的心血管疾病和危险因素。我们的总体目标是确定潜在的关键机制Ablation诱导的微血管损伤，并系统地研究心血管危险因素如何调节Ablation对内皮功能，氧化应激和血管炎症的影响。我们推测，黄芪通过氧化应激和激活晚期糖基化终产物受体（receptor for advanced glycation end products，ERK）和核因子κ B（nuclear factor kappa B，NF-κ B）信号通路诱导内皮功能障碍和血管炎症，高血糖（glycemic，HG）和棕榈酸（palmitic acid，PA）通过调节脑和外周脂肪小动脉中的这些通路而加重黄芪的血管毒性。在目的1中，我们将量化暴露于A10 ± HG或PA）对取自AD、轻度认知障碍（MCI）和认知正常（CN）受试者的柔脑膜小动脉的血管功能的影响，同时鉴定调节反应的关键炎症和氧化应激信号传导机制。在目的2中，我们将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，以研究中枢脑小动脉对AD应激源的反应，通过比较暴露于A β ± HG或PA的尸体和活体脂肪小动脉与尸体软脑膜小动脉中的血管、氧化应激和炎症信号传导反应。该建议将提供新的机制的关键相互作用和调制效果的见解 的心血管危险因素和人类微血管上的血管紧张素转换酶，同时比较血管反应，已知的AD应激源之间的AD，MCI和CN科目。脂肪小动脉作为脑微血管可接受的替代物的验证将提供一个实用的人类模型，以研究AD应激源引起的早期血管损伤的机制和治疗。

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.