Investigating neutrophilic inflammation as an APOE genotype-specific mediator of cognitive decline and reduced synaptic plasticity in aging

项目总结 载脂蛋白E的epsilon4等位基因(Apo4)的存在是晚发的最大遗传风险因素 阿尔茨海默病，与APOE4纯合子相比，风险增加约12倍 最常见的APOE3/APOE3基因。然而，不同的载脂蛋白E等位基因 对阿尔茨海默氏症风险的调节尚不清楚。这项研究的总体目标是：1)研究中性粒细胞 激活和寿命作为减少阿尔茨海默病风险或进展的治疗目标 不同的载脂蛋白E基因类型，以及2)确定代表有希望减少的目标的微生物相互作用 不同载脂蛋白E基因背景下的中性粒细胞炎症。大量数据表明， 不同载脂蛋白E基因型个体对炎性刺激的反应不同，载脂蛋白E- 调节的神经炎症正在成为载脂蛋白E特异性认知功能下降的潜在新的介体。 我们认为胃肠道和外周免疫系统可能是 感染或微生物失调和神经炎症，以及中性粒细胞，作为最丰富的 白细胞具有极大的炎症损伤潜力，可介导患者的反应改变 不同的载脂蛋白E等位基因会导致认知能力下降。我们的假设是APOE4增加了中性粒细胞 胃肠道、外周和大脑的激活和寿命，从而导致认知能力下降和减少 携带APOE4等位基因个体的突触可塑性。这一假设是基于令人信服的证据 发表的工作和我们的初步数据。研究表明，中性粒细胞渗入大脑。 AD期间的血管和实质以及周围的中性粒细胞激活对应于 阿尔茨海默病的疾病进展。我们的初步数据表明，载脂蛋白E改变了中性粒细胞的激活 炎症刺激以同型特异性的方式，正如先前在神经胶质细胞中观察到的那样。我们会 通过追求以下三个目标来解决我们的假设并实现我们的研究目标：1)检查 中性粒细胞在胃肠道、外周和脑中的激活、寿命和功能 在内源性启动子(APOE-tr)作用下表达人APOE2、APOE3和APOE4的小鼠； 微生物群和细菌-中性粒细胞相互作用在APOE特异性中性粒细胞中的作用 改变，以及3)确定中性粒细胞是否介导了APOE的神经炎症和认知功能下降- 通过中性粒细胞耗竭研究对低水平炎症刺激的特定反应方式。这个项目 是有意义的，因为没有研究研究APOE特异性的中性粒细胞反应，尽管提出了作用 阿尔茨海默病患者的中性粒细胞。这个项目在翻译上具有创新性和可操作性，因为 所获得的信息将为中性粒细胞靶向或微生物靶向治疗方法的测试提供信息 阿尔茨海默病小鼠模型和人类，并确定它们是否应该基于APOE进行定制 基因分型。

PROJECT SUMMARY The presence of the epsilon4 allele of APOE (APOE4) is the greatest genetic risk factor for late onset Alzheimer’s disease, increasing the risk approximately 12-fold when homozygous for APOE4 compared to the most common APOE3/APOE3 genotype. However, the mechanisms by which different APOE alleles mediate Alzheimer’s risk is unclear. The overall goals for this study are to 1) Investigate neutrophil activation and lifespan as therapeutic targets to reduce Alzheimer’s disease risk or progression in the context of different APOE genotypes and 2) Identify microbial interactions that represent promising targets to reduce neutrophilic inflammation in the context of different APOE genotypes. A multitude of data demonstrate that individuals with different APOE genotypes vary in their responses to inflammatory stimuli, and ApoE- modulated neuroinflammation is emerging as a potential new mediator of ApoE-specific cognitive decline. We propose that the gastrointestinal and peripheral immune systems represent a likely bridge between infection or microbial dysbiosis and neuroinflammation, and that neutrophils, as the most abundant leukocyte with great potential for inflammatory damage, mediate altered responses in individuals with different APOE alleles to drive cognitive decline. Our hypothesis is that APOE4 increases neutrophil activation and lifespan in the GI, periphery, and brain, thus contributing to cognitive decline and reduced synaptic plasticity in individuals with the APOE4 allele. This hypothesis is based on compelling evidence from published work and our preliminary data. Studies have demonstrated that neutrophils infiltrate the brain vasculature and parenchyma during AD and neutrophil activation in the periphery corresponds with disease progression in AD. Our preliminary data suggests that ApoE alters neutrophil activation to inflammatory stimuli in an isotype-specific manner, as has been observed previously in glial cells. We will address our hypothesis and achieve our study goals by pursuing the following three aims: 1) Examine neutrophil activation, lifespan, and function in the GI tract, periphery, and brain throughout the lifespan in mice expressing human APOE2, APOE3, and APOE4 under the endogenous promotor (APOE-TR); 2) Investigate roles of the microbiome and bacteria-neutrophil interactions in APOE-specific neutrophil alterations, and 3) Determine if neutrophils mediate neuroinflammation and cognitive decline in an APOE- specific manner in response to low level inflammatory stimuli via neutrophil depletion studies. This project is significant because no studies have investigated APOE-specific neutrophil responses despite a proposed role for neutrophils in Alzheimer’s disease. This project is translationally innovative and actionable because the information gained will inform the testing of neutrophil-targeted or microbial-targeted therapeutic approaches in Alzheimer’s disease mouse models and humans and determine if they should be tailored based on APOE genotype.