Identification of High Fat Diet Induced Modulations of the Gut-Brain Pathways

项目摘要 APOE 4是阿尔茨海默病（AD）最强的遗传风险因子，肥胖是最常见的遗传风险因子之一 AD的环境风险因素14%的人口是APOE 4携带者，30%的人口 对于患有肥胖症的人来说，了解这两种常见的AD风险因素如何相互作用是非常重要的。 我们将在健康啮齿动物模型中分析这些相互作用。先前的小鼠研究表明， 肥胖和APOE 4的结合进一步加剧了AD病理学和认知能力下降; 本文提出的目的是了解AD发病前发生的变化。APOE 3和APOE 4基因敲入小鼠 从6个月大时开始，给予高脂肪“西方”饮食（HFD，45%脂肪）12周。检查目标1a 与HFD相关的代谢和认知障碍，我们发现HFD增加了代谢 在APOE 3和APOE 4小鼠中，APOE 4小鼠更容易受到干扰。目标1b检查 HFD对胶质细胞免疫反应性、脂滴积聚和神经元复杂性的影响。我们找到HFD了 APOE 3和APOE 4小鼠中的胶质细胞免疫反应性和脂滴（LD）蓄积增加。的 我的论文的其余部分将集中在确定神经胶质细胞免疫反应性和LD的机制 积累和减少HFD诱导的改变。目标2a将检查平行的外周代谢和 HFD诱导的炎症通路。我们将研究：1）对于HFD，是特定的炎症或代谢 基因改变？2)外周和中枢神经系统特异性基因改变是否与HFD相关？ 3)HFD改变的特定基因在APOE 3和APOE 4基因型之间是否有差异？目标2b将审查 LD组成是否在基因型和饮食之间存在差异，以及LD积累的增加是否与 氧化应激。我们将研究：1）LD组成是否在APOE基因型和饮食之间存在差异？（二） LD积累与氧化应激增加相关吗？3)LD与活性氧共定位吗 物种？目的2c将检查Metastasis是否会改善LD积聚和与之相关的神经胶质增生。 关于HFD我们将研究：1）Metastasis是否减少胶质增生和LD积累？2)LD是否共定位 小胶质细胞或星形胶质细胞完成博士学位后，我将继续在博士后环境中培养技能 通过代谢组学研究饮食诱导认知改变的机制， 转录组学我将通过首先确定一个理想的博士后实验室，然后获得 博士后职位。我的目标是在一个重视 严谨的科研、创新、培训和专业发展。获得该 为了获得奖学金，我的赞助商和我已经承诺了一个计划，其中包括确定一个理想的实验室设置。我们 我同意与我的委员会成员和合作者一起工作，参加多个会议 和网络活动，并邀请演讲者。F99/K 00将极大地帮助我完成博士学位 并获得了我正在争取的博士后职位。

Project Summary APOE4 is the strongest genetic risk factor for Alzheimer’s Disease (AD) and obesity is one of the most common environmental risk factors for AD. With 14% of the population being APOE4 carriers and 30% of the population suffering from obesity, it is extremely important to understand how these two common AD risk factors interact. We will analyze these interactions in healthy rodent models. Previous studies in mice have shown the combination of obesity and APOE4 further exacerbates AD pathology and cognitive decline; the studies proposed here aim at understanding alterations that occur before AD onset. APOE3 and APOE4 knock-in mice were placed on high fat “western” diets (HFD, 45% fat) for 12 weeks starting at 6 months old. Aim 1a examined the metabolic and cognitive disturbances associated with HFD and we found HFD increased metabolic disturbances in APOE3 and APOE4 mice, with APOE4 mice being more susceptible. Aim 1b examined effects of HFD on glial immunoreactivity, lipid droplet accumulation, and neuronal complexity. We found HFD increased glia immunoreactivity and lipid droplet (LD) accumulation in APOE3 and APOE4 mice. The remainder of my thesis will focus on identifying mechanisms underlying glia immunoreactivity and LD accumulation and reducing HFD induced alterations. Aim 2a will examine parallel peripheral metabolic and inflammatory pathways induced by HFD. We will investigate: 1) With HFD, are specific inflammatory or metabolic genes altered? 2) Is there a correlation between the specific genes altered in the periphery and CNS with HFD? 3) Do the specific genes altered by HFD differ between APOE3 and APOE4 genotypes? Aim 2b will examine whether LD composition differs between genotypes and diets, and if increases in LD accumulation is associated with oxidative stress. We will investigate: 1) Does LD composition differ between APOE genotype and diet? 2) Does LD accumulation correlate with increased oxidative stress? 3) Do LDs colocalize with reactive oxygen species? Aim 2c will examine whether Metformin will ameliorate the LD accumulation and gliosis associated with HFD. We will investigate: 1) Does Metformin reduce gliosis and LD accumulation? 2) Do LDs co-localize with microglia or astrocytes? After completing my PhD, I will continue to build skills in a post-doctoral setting researching the mechanisms underlying diet induced cognitive alterations through metabolomics and transcriptomics. I will be successful in this through first identifying an ideal post-doctoral lab then obtaining the post-doctoral position. My goal is to complete my post-doctoral fellowship at an institution that values rigorous scientific research, innovation, training and professional development. To obtain this fellowship, my sponsor and I have committed to a plan that includes identifying an ideal lab setting. We have agreed to working with my committee members and collaborators, attending multiple conferences and networking events, and inviting speakers. The F99/K00 will greatly assist me in both completing my PhD and obtaining the postdoctoral position I am striving for.