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.

项目摘要/摘要 由异常聚集的淀粉样蛋白β蛋白沉积和神经原纤维缠结组成的淀粉样斑块 (NFTS)由脑中过度磷酸化的tau蛋白异常聚集组成，主要有两种 阿尔茨海默病(AD)患者的病理变化。伴发淀粉样斑块和神经营养不良 以小胶质细胞激活和细胞因子增加为特征的慢性炎症。造成这一现象的原因 绝大多数AD病例不明，有令人满意的AD治疗和预防措施 不可用。因此，迫切需要确定增加高血压风险的分子机制。 绝大多数阿尔茨海默病病例和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，肥胖被认为是高达70%-90%的原因 在2型糖尿病(T2 DM)病例中。高脂饮食(HFD)的摄入与 肥胖与2型糖尿病的关系。肥胖和2型糖尿病与老年人和强者的认知功能下降有关 AD的危险因素。此外，AD患者表现出葡萄糖摄取和胰岛素敏感性的降低 并增加了患T2 DM的风险。此外，肥胖和2型糖尿病是主要的血管风险。 并产生包括血脑屏障(BBB)在内的一系列宏微血管并发症 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、肥胖和全身炎症导致血液灌流不足、缺氧和血脑屏障功能障碍，从而导致 血脑屏障的Aβ清除减少，脑Aβ的积累和NFT的形成，导致 神经退化，最终导致阿尔茨海默病。我们假设血液细胞外小泡(EVS) 与肥胖和T2 DM相关的具有诱导血脑屏障的RNA和/或蛋白质谱特征 功能障碍、大脑葡萄糖代谢不足和脑内神经炎症，导致风险增加 加速AD的进展。在EV中大量发现的RNA和蛋白质在细胞- 参与免疫调节、炎症反应、细胞代谢、 代谢综合征和神经紊乱。为了验证这一假设，我们将从 高脂饲料喂养和正常饮食(NCD)喂养的小鼠，静脉注射EV到AD模型小鼠，并确定 体重、糖代谢、血脑屏障改变、AD样和炎性病理及行为功能 (目标1)。我们将测定AD模型、HFD和NCD喂养的小鼠血液中EV的蛋白质和RNA图谱 并进行信号通路分析(目标2)。这项研究的直接目标是确定 慢性摄入HFD产生的血液EVS在AD发病机制中的作用。如果被证实是真的，这个项目将 开辟新的研究途径来识别电动汽车中的特定分子(microRNAs和/或蛋白质)，这些分子是 负责增加肥胖和T2 DM患者患AD的风险，并最终预防和治疗AD。