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

研究中性粒细胞炎症作为衰老过程中认知能力下降和突触可塑性降低的 APOE 基因型特异性介质

• 批准号: 10670499
• 负责人: Tiffany Hensley-Mcbain
• 金额: $ 45万
• 依托单位: MC LAUGHLIN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670499
• 关键词: Address; Age; Age-Years; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Apolipoprotein E; Apoptosis; Automobile Driving; Bacteria; Behavioral; Blood; Brain; Cerebrovascular system; Chronic; Coculture Techniques; Colon; Data; Disease; Disease Progression; Electrophysiology (science); Feces; Freezing; Functional disorder; Gastrointestinal tract structure; Genes; Genotype; Goals; Health; Histologic; Human; Immune system; Impaired cognition; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Intraperitoneal Injections; LDL-Receptor Related Protein 1; Late Onset Alzheimer Disease; Lead; Leukocytes; Ligands; Longevity; Mediating; Mediator of activation protein; Memory Loss; Modeling; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neutrophil Activation; Neutrophilic Infiltrate; Outcome; Pathology; Peripheral; Persons; Phagocytes; Play; Publishing; Ribosomal DNA; Risk; Role; Senile Plaques; Signal Transduction; Stimulus; Synapses; Synaptic plasticity; Testing; Time; Tissues; United States; Work; base; body system; brain parenchyma; brain tissue; cell type; commensal bacteria; cytokine; dysbiosis; experimental study; gastrointestinal; genetic risk factor; innovation; jejunum; microbial; microbiome; microbiome alteration; microorganism interaction; mouse model; neuroinflammation; neutrophil; promoter; relating to nervous system; response; targeted treatment; theories; therapeutic target

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.

项目摘要 载脂蛋白E ε 4等位基因（APOE 4）的存在是晚发型最大的遗传危险因素 阿尔茨海默氏病，当APOE 4纯合子时，与APOE 4纯合子相比， 最常见的APOE 3/APOE 3基因型。然而，不同的载脂蛋白E等位基因 介导阿尔茨海默氏症的风险尚不清楚。本研究的总体目标是：1）研究中性粒细胞 激活和寿命作为治疗靶点以降低阿尔茨海默病的风险或进展 2）确定微生物之间的相互作用，代表有希望的目标，以减少 不同APOE基因型背景下的嗜酸性炎症大量数据表明， 具有不同APOE基因型的个体对炎症刺激的反应不同，ApoE- 受调节的神经炎症正在成为ApoE特异性认知下降的潜在新介质。 我们认为胃肠道和外周免疫系统可能是 感染或微生物生态失调和神经炎症，而嗜中性粒细胞作为最丰富 白细胞具有很大的炎症损伤潜力，可介导 不同的APOE等位基因导致认知能力下降。我们的假设是APOE 4增加了中性粒细胞 激活和寿命在胃肠道，外周，和大脑，从而有助于认知能力下降和减少 APOE 4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，中性粒细胞浸润大脑 血管和实质在AD和中性粒细胞活化在外周符合 AD的疾病进展。我们的初步数据表明，ApoE改变中性粒细胞活化， 正如之前在神经胶质细胞中观察到的那样，炎症刺激以同种型特异性的方式进行。我们将 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 中性粒细胞活化、寿命和在胃肠道、外周和脑中的功能 在内源性启动子（APOE-TR）下表达人APOE 2、APOE 3和APOE 4的小鼠; 2） 研究微生物组和细菌-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，和3）确定是否中性粒细胞介导的神经炎症和认知能力下降的APOE- 通过中性粒细胞耗竭研究，以特异性方式响应低水平炎症刺激。这个项目 是重要的，因为没有研究调查APOE特异性中性粒细胞反应，尽管提出了作用 嗜中性粒细胞在阿尔茨海默病中的作用该项目具有创新性和可操作性，因为 所获得的信息将为测试嗜中性粒细胞靶向或微生物靶向治疗方法提供信息， 阿尔茨海默病小鼠模型和人类，并确定是否应该根据APOE定制它们 基因型