Role of extracellular vesicles in the high-fat diet-induced risk of Alzheimer disease

项目概要/摘要 由异常聚集的淀粉样β蛋白沉积物和神经纤维缠结组成的淀粉样斑块 由脑中过度磷酸化的tau蛋白的异常聚集体组成的NFT是两种主要的神经功能缺损。 阿尔茨海默病（AD）患者的病理变化。淀粉样斑块和NFT伴随 慢性炎症的特征是小胶质细胞活化和细胞因子增加。的原因 绝大多数AD病例是未知的， 不可用.因此，迫切需要确定增加癌症风险的分子机制。 绝大多数AD病例以及制定预防和治疗措施。超过30%的 在美国，成年人目前被归类为肥胖， 2型糖尿病（T2 DM）病例。高脂肪饮食（HFD）的摄入与以下因素密切相关： 肥胖和T2 DM。肥胖和T2 DM与老年人认知功能下降有关， AD的危险因素此外，AD患者显示出葡萄糖摄取和胰岛素敏感性降低， 大脑，并增加了患T2 DM的风险。此外，肥胖和T2 DM是主要的血管风险 因素，并产生许多大血管和微血管并发症，包括血脑屏障（BBB） 功能障碍和炎症。根据AD的血管假说，血管危险因素包括 糖尿病、肥胖和全身性炎症诱导低灌注、缺氧和BBB功能障碍， Aβ通过BBB的清除率降低，脑Aβ蓄积和NFT形成减少，导致 最终导致AD痴呆我们假设血细胞外囊泡（EV） 与肥胖和T2 DM相关的蛋白质具有诱导BBB的RNA和/或蛋白质谱的特征， 功能障碍、脑葡萄糖代谢低下和脑神经炎症，导致风险增加 加速AD的发展。在EV中大量发现的RNA和蛋白质在细胞中具有重要作用。 与细胞通讯，并参与免疫调节，炎症反应，细胞代谢， 代谢综合征和神经系统疾病。为了验证这一假设，我们将从血液中分离EV， HFD和正常食物饮食（NCD）喂养的小鼠，将EV静脉内输注到AD模型小鼠中，并测定 体重、葡萄糖代谢、BBB变化、AD样和炎症病理学以及行为功能 (Aim 1）。我们将确定AD模型、HFD和NCD喂养小鼠血液EV的蛋白质和RNA谱 并进行其信号通路分析（Aim 2）。本研究的直接目标是确定 在AD发病机制中由HFD的慢性消耗产生的血液EV。如果被证明是真的，这个项目将 开辟了新的研究途径，以确定电动汽车中的特定分子（microRNA和/或蛋白质）， 导致肥胖和T2 DM患者AD风险增加，并最终预防和治疗AD。

Project summary/Abstract Amyloid plaques composed of deposits of abnormally aggregated amyloid β-protein and neurofibrillary tangles (NFTs) consisting of abnormal aggregates of hyperphosphorylated tau protein in the brain are two main pathological changes in patients with Alzheimer's disease (AD). Amyloid plaques and NFTs are accompanied with chronic inflammation characterized by activated microglia and increased cytokines. The causes for the vast majority of AD cases are unknown and satisfactory therapeutic and preventive measures for AD are unavailable. Therefore, an urgent need exists to identify the molecular mechanisms that increase the risk for the vast majority of AD cases and for development of preventive and therapeutic measures. Over 30% of adults are currently classified as obese in the US and obesity is considered to be responsible for up to 70-90% of type 2 diabetes mellitus (T2DM) cases. Consumption of high fat diets (HFD) is strongly associated with obesity and T2DM. Obesity and T2DM are linked to decreases in cognitive functions in older adults and strong risk factors of AD. Furthermore, AD patients show decreases in glucose uptake and insulin sensitivity in the brain and have increased risk for developing T2DM. Additionally, obesity and T2DM are main vascular risk factors and produce a number of macro- and micro-vascular complications including blood-brain barrier (BBB) dysfunction and inflammation. According to the vascular hypothesis of AD, vascular risk factors including diabetes, obesity and systemic inflammation induce hypoperfusion, hypoxia and BBB dysfunction, which cause reduced Aβ clearance across the BBB, accumulation of brain Aβ, and NFT formation, leading to neurodegeneration and, ultimately, AD dementia. We hypothesize that blood extracellular vesicles (EVs) associated with obesity and T2DM have the characteristics of RNA and/or protein profiles that induce the BBB dysfunction, brain glucose hypometabolism and neuroinflammation in the brain, leading to an increased risk and accelerated progression of AD. RNAs and proteins abundantly found in EVs have important roles in cell- to-cell communication and are involved in immune regulation, inflammatory responses, cell metabolism, metabolic syndrome and neurological disorders. In order to test the hypothesis, we will isolate blood EVs from HFD- and normal chow diet (NCD)-fed mice, intravenously infuse the EVs into AD model mice and determine body weight, glucose metabolism, BBB changes, AD-like and inflammatory pathology and behavioral functions (Aim 1). We will determine protein and RNA profiles of blood EVs from AD model, HFD- and NCD-fed mice and perform their signaling pathway analysis (Aim 2). The immediate goal of this study is to determine the role of blood EVs produced by chronic consumption of HFD in the AD pathogenesis. If proven true, this project will open new research avenues to identify specific molecules (microRNAs and/or proteins) in EVs, which are responsible for the increased risk of AD in obese and T2DM patients and to ultimately prevent and treat AD.