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

描述（由申请人提供）：大多数散发性阿尔茨海默病（SAD）病例发病机制的分子机制在很大程度上是未知的;多种环境因素（如饮食和生活方式）与遗传因素之间的复杂相互作用沿着都是重要的影响因素。经典的心脏代谢风险因素，如高血压、糖尿病和高胆固醇血症，也已被证明会增加SAD的风险，并具有几个常见特征，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）与生理相关的高胆固醇含量的组合， 一氧化氮合酶基因（eNOS）诱导显著的AD样表型，包括淀粉样蛋白生成增加、代谢变化和神经炎症。我们假设，通过将总体血管风险因素与长期TWD（>8个月）相结合，我们将在中年非转基因C57 BL/6小鼠中创建SAD的代表性非转基因小鼠模型。为了验证这一假设，提出了两个具体目标，即1）通过各种行为测试确定eNOS缺陷小鼠（eNOS-/-和eNOS+/-）中TWD对AD相关认知测量的影响，以及2）全面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，以解开心血管疾病，糖尿病和AD之间的进一步机制关联。许多已鉴定的糖尿病基因作为AD风险基因的验证将鼓励我们在未来使用该模型进行全基因组基因分析，以鉴定新的AD血管代谢风险基因。

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.