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

细胞外囊泡在高脂肪饮食诱发的阿尔茨海默病风险中的作用

• 批准号: 9385535
• 负责人: Ken-ichiro Fukuchi
• 金额: $ 19.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9385535
• 关键词: ABCC1 gene; ABCG2 gene; Adult; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Animals; Behavioral; Binding; Blood; Blood - brain barrier anatomy; Blood Vessels; Body Weight; Brain; C57BL/6 Mouse; Cell Communication; Cell physiology; Cells; Cellular Metabolic Process; Cerebrum; Characteristics; Chronic; Cognitive deficits; Consumption; Dementia; Deposition; Development; Diabetes Mellitus; Diet; Elderly; Endothelial Cells; Energy Metabolism; Epidemic; Functional disorder; Glucose; Glucose Transporter; Goals; High Fat Diet; Human; Hypoxia; Immune response; Impaired cognition; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Intravenous; Late Onset Alzheimer Disease; Lead; Lesion; Link; Lipopolysaccharides; Measures; Metabolic syndrome; MicroRNAs; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; P-Glycoprotein; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway Analysis; Patients; Peripheral; Permeability; Physiological Processes; Preventive; Preventive measure; Production; Proteins; RNA; Reporting; Research; Research Project Grants; Risk; Risk Factors; Rodent; Role; SLC2A1 gene; Senile Plaques; Signal Pathway; Testing; Therapeutic; Tight Junctions; amyloid pathology; brain parenchyma; cell type; circulating microRNA; cognitive function; cytokine; diabetic; diabetic rat; exosome; extracellular vesicles; glucose metabolism; glucose uptake; hyperphosphorylated tau; hypoperfusion; immunoregulation; impaired glucose tolerance; improved; insulin sensitivity; member; microvesicles; mouse model; nervous system disorder; neurofibrillary tangle formation; neuroinflammation; occludin; prevent; protein profiling; tau Proteins; trend; uptake

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.

项目概要/摘要 淀粉样斑块由异常聚集的淀粉样 β 蛋白和神经原纤维缠结组成 （NFT）由大脑中过度磷酸化 tau 蛋白的异常聚集体组成，主要有两种 阿尔茨海默病（AD）患者的病理变化。淀粉样斑块和 NFT 伴随 以小胶质细胞激活和细胞因子增加为特征的慢性炎症。产生的原因 绝大多数AD病例是未知的，并且令人满意的AD治疗和预防措施 不可用。因此，迫切需要确定增加风险的分子机制。 绝大多数 AD 病例以及制定预防和治疗措施。超过30%的 目前在美国，成年人被归类为肥胖，肥胖被认为是造成高达 70-90% 的原因 2 型糖尿病 (T2DM) 病例。高脂肪饮食 (HFD) 的消耗与 肥胖和 T2DM。肥胖和 T2DM 与老年人认知功能下降有关 AD 的危险因素。此外，AD 患者的葡萄糖摄取和胰岛素敏感性降低 脑，并增加患 T2DM 的风险。此外，肥胖和 T2DM 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、肥胖和全身炎症会导致低灌注、缺氧和血脑屏障功能障碍，从而导致 跨 BBB 的 Aβ 清除减少、大脑 Aβ 积累和 NFT 形成减少，导致 神经退行性疾病，最终导致 AD 痴呆。我们假设血液细胞外囊泡（EV） 与肥胖和 T2DM 相关的 RNA 和/或蛋白质谱特征可诱导 BBB 功能障碍、脑葡萄糖代谢低下和大脑神经炎症，导致风险增加 并加速 AD 的进展。 EV 中大量存在的 RNA 和蛋白质在细胞- 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。为了检验这一假设，我们将从中分离出血液 EV HFD 和正常饮食 (NCD) 喂养的小鼠，将 EV 静脉注射到 AD 模型小鼠中并确定 体重、葡萄糖代谢、BBB 变化、AD 样和炎症病理学以及行为功能 （目标 1）。我们将确定 AD 模型、HFD 和 NCD 喂养小鼠的血液 EV 的蛋白质和 RNA 谱 并进行信号通路分析（目标 2）。这项研究的直接目标是确定角色 AD 发病机制中长期食用 HFD 产生的血液 EV。如果证实属实，该项目将 开辟新的研究途径来识别 EV 中的特定分子（microRNA 和/或蛋白质），这些分子是 负责增加肥胖和 T2DM 患者患 AD 的风险，并最终预防和治疗 AD。