AD pathogenesis in a novel mouse diet model with a partial eNOS deficiency

部分 eNOS 缺乏的新型小鼠饮食模型中的 AD 发病机制

• 批准号: 8550749
• 负责人: Francesca-Fang Liao
• 金额: $ 17.72万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550749
• 关键词: Ablation; Adult; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Animals; Behavioral; Behavioral Assay; Biochemical; Blood Vessels; Brain; C57BL/6 Mouse; Cardiovascular Diseases; Cessation of life; Cholesterol; Chronic; Cleaved cell; Cognitive; Combined Modality Therapy; Complex; Consumption; Development; Diabetes Mellitus; Diet; Diet Habits; Environmental Risk Factor; Enzymes; Fatty acid glycerol esters; Functional disorder; Future; Gene Delivery; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Human; Hyperglycemia; Hypertension; Impaired cognition; Incidence; Individual; Insulin Resistance; Learning; Life Style; Link; Measures; Mediating; Memory; Metabolic; Milk; Modeling; Molecular; Mus; Nitric Oxide; Nitric Oxide Synthase; Obesity; Outcome; Oxidative Stress; Pathogenesis; Patients; Performance; Phase; Phenotype; Pilot Projects; Play; Population; Regulation; Reporting; Reproducibility; Research; Risk; Risk Factors; Role; Signal Transduction; Site; Synapses; Testing; Time; Validation; Western World; Work; amyloidogenesis; astrogliosis; base; behavior test; beta-site APP cleaving enzyme 1; clinically relevant; cognitive change; cognitive function; cohort; diabetic; feeding; genome-wide; human NOS3 protein; hypercholesterolemia; middle age; mouse model; neuroinflammation; neurotoxicity; novel; small hairpin RNA; success; tau Proteins; tool

DESCRIPTION (provided by applicant): The molecular mechanisms underlying pathogenesis in the majority of sporadic Alzheimer's disease (SAD) cases are largely unknown; complex interactions between multiple environmental factors, such as diet and life style, along with genetic factors are all significant contributors. Classic cardio-metabolic risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia have also been shown to increase the risk of SAD with several common features, including insulin resistance, neuroinflammation and endothelial dysfunction. Our pilot study indicates that combination of a typical Western diet (TWD) with physiologically relevant high cholesterol content with mice deficient in vascular nitric oxide synthase gene (eNOS) induces significant AD-like phenotypes including increased amyloidogenesis, metabolic changes and neuroinflammation. We hypothesize that by combining the global vascular risk factor with long-term TWD (>8 months), we will create a representative non-transgenic mouse model for SAD in middle-aged non-transgenic C57BL/6 mice. To test this hypothesis, two specific aims are proposed accordingly to 1) determine the effects of a TWD in eNOS-deficient mice (eNOS-/- and eNOS+/-) on AD-related cognitive measures by various behavioral tests and 2) to comprehensively characterize AD-like phenotypes in the selected diet model. Given our success, the model will provide a useful tool to unravel further mechanistic associations between cardiovascular diseases, diabetes and AD. Validation of a number of identified diabetic genes as AD risk genes will encourage us to use this model in the future to conduct a genome- wide gene analysis to identify new vascular-metabolic risk genes for AD.

描述(由申请人提供)：在大多数散发性阿尔茨海默病(SAD)病例中，其发病的分子机制在很大程度上是未知的；多种环境因素之间的复杂相互作用，如饮食和生活方式，以及遗传因素，都是重要的因素。经典的心脏代谢危险因素，如高血压、糖尿病和高胆固醇血症，也被证明会增加SAD的风险，并具有几个共同特征，包括胰岛素抵抗、神经炎症和内皮功能障碍。我们的初步研究表明，典型的西方饮食(TWD)与生理上相关的高胆固醇含量与血管一氧化氮缺乏的小鼠相结合 氧化氮合酶基因(ENOS)可诱导显著的AD样表型，包括淀粉样蛋白合成增加、代谢改变和神经炎症。我们假设，通过将全球血管危险因素与长期TWD(&gt；8个月)相结合，我们将在中年非转基因C57BL/6小鼠中创建具有代表性的非转基因SAD小鼠模型。为了验证这一假说，提出了两个具体的目标：1)通过各种行为测试，确定eNOS缺陷小鼠的TWD(eNOS-/-和eNOS+/-)对AD相关认知指标的影响；2)综合表征所选饮食模型中的AD样表型。鉴于我们的成功，该模型将提供一个有用的工具，进一步揭示心血管疾病、糖尿病和阿尔茨海默病之间的机械联系。一些已识别的糖尿病基因被确认为AD危险基因将鼓励我们在未来使用这一模型进行全基因组基因分析，以识别新的AD血管代谢危险基因。