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 由绝对聚集的淀粉样蛋白β-蛋白质和神经原纤维缠结的沉积物组成的淀粉样蛋白斑块 （NFTS）由大脑中高磷酸化tau蛋白的异常聚集体组成，是两个主要 阿尔茨海默氏病（AD）患者的病理变化。淀粉样斑块和NFT伴随 慢性炎症的特征是活化的小胶质细胞和增加的细胞因子。原因 绝大多数AD病例都是未知的，令人满意的AD治疗和预防措施是 不可用。因此，迫切需要确定增加的分子机制 绝大多数AD病例以及预防和治疗措施的发展。超过30％ 目前，成人在美国被归类为肥胖，肥胖被认为负责高达70-90％ 2型糖尿病（T2DM）病例。消费高脂饮食（HFD）与 肥胖和T2DM。肥胖和T2DM与老年人认知功能的降低有关 AD的风险因素。此外，AD患者在葡萄糖摄取和胰岛素敏感性的下降 大脑并增加了开发T2DM的风险。此外，肥胖和T2DM是主要的血管风险 因素并产生许多宏观和微血管并发症，包括血脑屏障（BBB） 功能障碍和炎症。根据AD的血管假设，血管风险因素包括 糖尿病，肥胖和全身性炎症会引起炎症，缺氧和BBB功能障碍，这会导致引起 降低了整个BBB的Aβ间隙，脑Aβ的积累和NFT形成，导致 神经变性，最终是AD痴呆症。我们假设血液外蔬菜（EV） 与肥胖和T2DM相关的具有影响BBB的RNA和/或蛋白质曲线的特征 大脑功能障碍，脑葡萄糖低代谢和神经炎症，导致风险增加 和AD的加速进展。 EV中发现的RNA和蛋白质绝对具有重要作用在细胞中 待办事项通信，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。为了检验假设，我们将使血液电动汽车与 HFD和正常食物饮食（NCD）喂养小鼠，将电动汽车静脉注射到AD模型中并确定 体重，葡萄糖代谢，BBB变化，类似广告样和炎症病理和行为功能 （目标1）。我们将确定来自AD模型，HFD和NCD-FED小鼠的血液电动汽车的蛋白质和RNA谱。 并执行其信号通路分析（AIM 2）。这项研究的直接目标是确定角色 通过在AD发病机理中长期消费HFD产生的血液电动汽车。如果被证明是正确的，这个项目将 开放新的研究途径，以鉴定电动汽车中的特定分子（microRNA和/或蛋白质） 负责肥胖和T2DM患者的AD风险增加，并最终预防和治疗AD。