Synergistic effect of APOE genotype and obesity in CNS inflammation and risk of Alzheimer's disease

APOE 基因型和肥胖对中枢神经系统炎症和阿尔茨海默病风险的协同作用

• 批准号: 10458780
• 负责人: G WILLIAM REBECK
• 金额: $ 19.5万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458780
• 关键词: Address; Advanced Glycosylation End Products; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Anti-Inflammatory Agents; Apolipoprotein E; Applications Grants; Area; Behavioral Assay; Biological Assay; Biological Markers; Blood; Brain; Cells; Chronic; Complex; Data; Diabetes Mellitus; Diet; Disease; ERG gene; Early Intervention; Environment; Environmental Exposure; Environmental Risk Factor; FOS gene; Female; Future; Genes; Genetic; Genotype; High Density Lipoproteins; High Fat Diet; Human; I-kappa B Proteins; Immediate-Early Genes; Immunofluorescence Immunologic; Impaired cognition; In Situ Hybridization; Individual; Inflammation; Inflammatory; Intervention; Knock-in; Knock-in Mouse; Lesion; Life; Macronutrients Nutrition; Measures; Messenger RNA; Metabolic; Metabolic syndrome; Metformin; Microglia; Modeling; Morphology; Mus; Nervous System Trauma; Neuroglia; Obesity; Pathologic; Pathway interactions; Penetrance; Peptides; Peripheral; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Plasma; Population; Pre-Clinical Model; Property; Protein Isoforms; Proteins; Risk; Risk Factors; Rodent Model; Sampling; Severities; Signal Pathway; Standardization; Structure; Subgroup; Technology; Testing; Time; Transcript; Traumatic Brain Injury; aging brain; apolipoprotein E-4; base; cell motility; comorbidity; density; driving force; experience; functional outcomes; genetic risk factor; genotypic sex; high risk; in vivo; inflammatory marker; male; mimetics; mouse model; nano-string; neurochemistry; neuroinflammation; normal aging; personalized medicine; response; sex; western diet

PROJECT SUMMARY We have previously pursued the hypothesis that APOE genotype alters normal brain neurochemistry and structure early in life, generating an environment that alters the risk of Alzheimer’s Disease (AD) with aging. Studies with APOE knock-in mice have demonstrated that APOE genotype affects neuroinflammation in response to various neurological injuries in an isoform-specific manner, with apoE4 displaying the least anti- inflammatory activity. Inflammation is also a consequence of several environmental risk factors for AD, such as traumatic brain injury, obesity, and metabolic syndrome. Obesity is the strongest environmental risk factor for AD. With 14% of the US population being APOE4 carriers and 35% of the population suffering from obesity, it is extremely important to understand how these two common AD risk factors synergize. Sex is also a critical variable in the risk of cognitive impairments, with females at significantly higher risk. Thus, the risk of AD depends on a complex set of connections between genetic, environmental, and sex effects. This project aims to analyze these interactions in healthy rodent models, thus providing early disease targets that could be use as markers of AD risk and as targets for disease intervention. Aim 1 will determine robust markers of neuroinflammation in APOE3 and APOE4 male and female mice after experiencing chronic peripheral inflammation induced by diet. We will test our hypothesis that specific neuroinflammatory pathways will be coordinately affected by these three AD risk factors. We have begun to identify neuroinflammatory pathways through non-directed transcript analysis, and we will test the rigor of those findings through qPCR. We will further refine specific neuroinflammatory pathways using immunofluorescence, in situ hybridization analyses, and kinase measures. Finally, we will define inflammatory cell responses by defining the density, morphology, and motility of the microglia using our model of CX3CR1GFP/+ mice on APOE3 and APOE4 knock-in backgrounds. Aim 2 will determine the effects of two safe, anti-inflammatory drugs on CNS inflammation markers in the subgroups of most affected APOE female and male mice. We will treat APOE3 and APOE4 mice on a high fat diet with metformin (a diabetes treatment) or 4F peptide (promoting high density lipoproteins). We will test our hypothesis that safe anti-inflammatory drugs could reduce the neuroinflammatory pathways most consistent with AD risk factors. These studies will refine the pathways identified in Aim 1, and further those findings by addressing whether there are functional CNS consequences of these treatments through behavioral assays. Furthermore, we will test whether any inflammation pathways identified in CNS correlate with effects in the blood using assays on plasma samples. By the end of this R21 study, we will have identified a subset of neuroinflammatory molecules that could be use as early markers of AD risk and defined whether anti- inflammatory approaches will be useful in personalized medicine approaches taking APOE genotype, diet, and sex into account.

项目总结 我们之前一直坚持这样的假设，即载脂蛋白E基因改变了正常的脑神经化学和 结构在生命早期，产生一个环境，改变阿尔茨海默病(AD)的风险随着年龄的增长。 对APOE基因敲入小鼠的研究表明，APOE基因影响脑神经炎症。 对各种神经损伤的反应是同型特异性的，apoE4显示的抗药性最低 炎症活动。炎症也是AD的几个环境风险因素的结果，例如 创伤性脑损伤、肥胖和代谢综合征。肥胖是最大的环境风险因素 广告。美国14%的人口是APOE4携带者，35%的人口患有肥胖症。 了解这两个常见的AD风险因素如何协同作用是极其重要的。性也是一个关键因素 认知障碍的风险存在差异，女性的风险明显更高。因此，AD的风险取决于 关于遗传、环境和性影响之间的一系列复杂联系。该项目旨在分析 在健康的啮齿动物模型中，这些相互作用，从而提供了可以用作标记的早期疾病靶点 并将其作为疾病干预的目标。AIM 1将确定强健的神经炎症标志物 APOE3和APOE4雄性和雌性小鼠在经历了饮食诱导的慢性外周炎症后。 我们将检验我们的假设，即特定的神经炎性通路将受到 这三个AD危险因素。我们已经开始通过非定向的方式识别神经炎性通路 转录本分析，我们将通过qPCR来测试这些发现的严谨性。我们将进一步细化具体的 使用免疫荧光、原位杂交分析和激酶测量的神经炎性通路。 最后，我们将通过定义炎症细胞的密度、形态和运动性来定义炎症细胞反应。 使用我们的CX3CR1GFP/+小鼠模型在APOE3和APOE4敲入背景上进行小胶质细胞的研究。目标2将 确定两种安全的抗炎药物对中枢神经系统炎症标志物的影响 受影响最严重的是雌性和雄性小鼠。我们将用高脂饮食治疗APOE3和APOE4小鼠 二甲双胍(一种治疗糖尿病的药物)或4F肽(促进高密度脂蛋白)。我们将测试我们的 假设安全的抗炎药物可以最大限度地减少神经炎性通路 符合AD风险因素。这些研究将完善目标1中确定的途径，并进一步 通过行为研究解决这些治疗是否有功能性中枢神经系统后果的发现 化验。此外，我们将测试在中枢神经系统中发现的任何炎症途径是否与 通过对血浆样本进行化验来检测血液。在此R21研究结束时，我们将确定以下内容的子集 神经炎性分子可作为AD风险的早期标志物，并定义是否抗AD 炎症方法将在个性化药物方法中有用，这些方法包括APOE基因、饮食和 把性考虑在内。