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

基本信息

批准号：
10300827
负责人：
G WILLIAM REBECK
金额：
$ 23.4万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10300827
关键词：
Address Advanced Glycosylation End Products Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目摘要我们以前曾提出过这样的假设，即APOE基因型改变了正常的脑神经化学和生命早期的结构，产生一个随着衰老而改变阿尔茨海默氏病（AD）风险的环境。对APOE敲门小鼠的研究表明，APOE基因型会影响神经炎症对各种神经系统损伤的反应，同工型特异性的方式，APOE4表现出最小的抗炎症活动。炎症也是AD的几个环境风险因素的结果，例如脑损伤，肥胖和代谢综合征。肥胖是强大的环境风险因素广告。 14％的美国人口是APOE4携带者和肥胖症患者的35％，这是了解这两个常见的AD风险因素如何协同作用非常重要。性也是关键认知障碍风险的变化，女性的风险明显更高。那，广告的风险取决于在遗传，环境和性别影响之间的一组复杂的联系上。该项目旨在分析这些相互作用在健康的啮齿动物模型中，因此提供了可以用作标记的早期疾病靶标 AD风险和作为疾病干预的目标。 AIM 1将确定神经炎症的鲁棒标记 APOE3和APOE4雄性和雌性小鼠在饮食引起的慢性外周炎症后。我们将检验我们的假设，即特定的神经炎症途径将受到协调的影响这三个AD风险因素。我们已经开始通过非指导识别神经炎症途径成绩单分析，我们将通过qPCR测试这些发现的严谨性。我们将进一步完善特定的使用免疫荧光，原位杂交分析和激酶测量的神经炎症途径。最后，我们将通过定义的密度，形态和运动来定义炎症细胞反应小胶质细胞使用我们在APOE3和APOE4敲入背景上的CX3CR1GFP/+小鼠模型。 AIM 2意志确定两种安全的抗炎药对CNS炎症标记的影响大多数受影响的Apoe雌性和雄性小鼠。我们将以高脂饮食对APOE3和APOE4小鼠进行治疗二甲双胍（糖尿病治疗）或4F胡椒（促进高密度脂蛋白）。我们将测试我们的假设安全的抗炎药可以减少神经炎症途径大多数与AD风险因素一致。这些研究将完善AIM 1中确定的途径，并进一步通过解决这些治疗方法是否有功能性中枢神经系统通过行为的后果，发现结果测定。此外，我们将测试中枢神经系统中发现的任何炎症途径是否与影响在血浆样品上使用阿萨斯的血液。到这项R21研究结束时，我们将确定一个子集可以用作AD风险的早期标志的神经炎症分子，并定义了抗以APOE基因型，饮食和性别。