Role of diet-induced miR-34a in Alzheimer disease and dementia

饮食诱导的 miR-34a 在阿尔茨海默病和痴呆中的作用

• 批准号: 9225329
• 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: 2017-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9225329
• 关键词: ABCC1 gene; ABCG2 gene; ATP binding cassette transporter 1; Adult; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Automobile Driving; Behavioral; Binding; Blood; Blood - brain barrier anatomy; Blood Glucose; Blood Vessels; Blood capillaries; Brain; Brain Injuries; Brain Ischemia; Cardiovascular Diseases; Cell Communication; Cell membrane; Cells; Cellular Metabolic Process; Cerebrovascular system; Chronic; Consumption; Control Groups; Deposition; Development; Diabetes Mellitus; Diet; Early Onset Familial Alzheimer' s Disease; Elderly; Endothelial Cells; Epidemic; Functional disorder; Goals; High Fat Diet; Homeostasis; Hypertension; Hypoxia; Impaired cognition; Impairment; Inflammation; Inflammatory Response; Insulin Resistance; Intravenous; LDL-Receptor Related Protein 1; Late Onset Alzheimer Disease; Lead; Link; Lipopolysaccharides; Lipoprotein Receptor; Maintenance; Measures; Mediating; Messenger RNA; Metabolic syndrome; MicroRNAs; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Neurotoxins; Non-Insulin-Dependent Diabetes Mellitus; Obesity; P-Glycoprotein; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Patients; Peripheral; Physiological Processes; Play; Preventive; Preventive measure; Production; Protein Precursors; Proteins; Research Project Grants; Risk; Risk Factors; Role; Route; Senile Plaques; Side; Signal Transduction; Stroke; Testing; Therapeutic; Vascular Dementia; Xenobiotics; abeta accumulation; beta catenin; brain endothelial cell; brain parenchyma; capillary; cell type; circulating microRNA; cognitive function; cytokine; early onset; efflux pump; exosome; extracellular vesicles; hyperphosphorylated tau; hypoperfusion; immunoregulation; inhibitor/antagonist; member; microvesicles; mouse model; nervous system disorder; neurofibrillary tangle formation; neuroinflammation; neurotoxic; protein B; protein oligomer; saturated fat; tau Proteins; therapeutic target; vascular inflammation

Project Summary / Abstract Patients with Alzheimer's disease (AD) develop two main pathological changes in the brain: amyloid plaques composed of deposits of abnormally aggregated amyloid β-protein (Aβ) and neurofibrillary tangles (NFTs) consisting of abnormal aggregates of hyperphosphorylated tau protein. Amyloid plaques and NFTs are accompanied with chronic inflammation characterized by activated microglia and increased cytokines. Except a small subset of early-onset familial AD cases, 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, insulin resistance and T2DM. Obesity and T2DM are main risk factors of AD, cognitive impairment, vascular dementia, cardiovascular disease, and stroke. Additionally, sustained alterations in blood glucose levels promote vascular inflammation and blood- brain barrier (BBB) impairment. Furthermore, the risk of AD increases with the number of vascular risk factors. According to the vascular hypothesis of AD, dysfunctional BBB play a causal role in the pathogenesis of AD, leading to accumulation of Aβ, neuroinflammation, neuronal dysfunction, neurodegeneration and, ultimately, dementia of AD. We recently found increased levels of microRNA-34a (miR-34a) in blood exosomes derived from animal models of AD, T2DM and peripheral inflammation. Blood miR-34a levels are elevated in patients with T2DM. We hypothesize that HFD and peripheral inflammation increase miR-34a in blood and increased levels of miR-34a in blood induce brain endothelial cell dysfunction (dysfunctional BBB), leading to an increased risk, early onset and accelerated progression of AD and that miR-34a can be a therapeutic target. This hypothesis will be tested by carrying out the following aims. In Aim 1, we will produce a miR-34a-deficient AD mouse model and determine the effects of miR-34a deficiency on AD-like pathology and cognitive functions. In Aim 2, we will prepare extracellular vesicles (EVs) loaded with miR-34a and its inhibitor, intravenously infuse the EVs and determine the effects of EVs loaded with miR-34a and its inhibitor on AD-like pathology and behavioral functions in an AD mouse model. The long-term goals of this project are to determine the role of miR-34a in the pathogenesis of AD and to develop new preventive and therapeutic strategies for AD.

项目摘要 /摘要 阿尔茨海默氏病（AD）患者发生了两种主要病理变化：淀粉样蛋白斑块 由绝对聚集的淀粉样蛋白β-蛋白（Aβ）和神经原纤维缠结（NFTS）的沉积物组成 由高磷酸化tau蛋白的异常聚集体组成。淀粉样斑块和NFT是 伴随着慢性炎症，其特征是活化的小胶质细胞和增加的细胞因子。除了 一小部分早期发作的家庭AD病例，绝大多数AD病例的原因是未知的，并且 令人满意的AD治疗和预防措施是不可用的。因此，迫切需要 确定增加绝大多数AD病例风险的分子机制和开发的风险 预防和治疗措施。当前，超过30％的成年人在美国被归类为肥胖， 肥胖被认为是2型糖尿病（T2DM）病例的70-90％的原因。 高脂饮食（HFD）的消费与肥胖，胰岛素抵抗和T2DM密切相关。肥胖 T2DM是AD，认知障碍，血管痴呆，心血管疾病和 中风。此外，血糖水平的持续改变会促进血管感染和血液 脑屏障（BBB）障碍。此外，AD的风险随血管危险因素的数量增加。 根据AD的血管假设，功能失调的BBB在AD的发病机理中起因果作用， 导致Aβ的积累，神经炎症，神经元功能障碍，神经变性以及最终 广告的痴呆症。我们最近发现血液外泌体中microRNA-34A（miR-34a）的水平升高 来自AD，T2DM和外周炎症的动物模型。患者血液miR-34a水平升高 使用T2DM。我们假设HFD和外周炎症会增加血液中的miR-34a并增加 血液中miR-34a的水平诱导脑内皮细胞功能障碍（功能障碍BBB），导致 AD的风险增加，早期发作和加速进展，而miR-34a可以成为治疗靶点。 该假设将通过执行以下目标来检验。在AIM 1中，我们将产生miR-34a缺乏效率 AD小鼠模型并确定miR-34a缺乏对AD样病理和认知功能的影响。 在AIM 2中，我们将准备带有miR-34a及其抑制剂的细胞外蔬菜（EV），静脉注射 电动汽车并确定带有miR-34a及其抑制剂对广告样病理学和 AD鼠标模型中的行为功能。该项目的长期目标是确定 miR-34a在AD的发病机理中，并为AD开发新的预防和治疗策略。