Human vascular model to study Alzheimer's Disease

描述(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。现已公认，血管功能障碍导致脑低血流灌注和血脑屏障功能受损在AD早期发生，并在早期病理生理学中起中心作用。AD研究中的关键障碍包括缺乏关于心血管危险因素如何导致AD或调节A？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，使用从器官捐赠者快速尸检中分离的体外软脑膜小动脉来研究微血管对A？和心血管危险因素的反应是可行的。我们的总体目标是确定A？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A？对内皮功能、氧化应激和血管炎症的影响。我们假设A？通过氧化应激、晚期糖基化终末产物受体(RAGE)和核因子-kappaB(NF-KB)信号的激活而导致内皮功能障碍和血管炎症，而高血糖(HG)和棕榈酸(PA)将通过调节脑和外周脂肪小动脉的这些途径而加重A？血管毒性。在目标1中，我们将量化暴露于Aç±HG或PA)对AD、轻度认知障碍(MCI)和认知正常(CN)受试者软脑膜小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。在目标2中，我们将通过比较身体和活体受试者脂肪小动脉与身体软脑膜小动脉的血管、氧化应激和炎症信号反应，来建立外周脂肪小动脉作为研究AD应激源的实用人类替代模型的有效性。该提案将为关键的相互作用和调节效应提供新的机械论见解 同时比较AD、MCI和CN受试者对已知AD应激源的血管反应。脂肪小动脉作为脑微血管替代物的有效性验证将为研究AD应激性早期血管损伤的机制和治疗提供一个实用的人体模型。

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.