Role of the Innate Immune System in Aging and Development of Alzheimer's Disease

描述（由申请人提供）：一个主要的健康问题涉及随着年龄的增长和阿尔茨海默病（AD）的威胁进行性认知下降。我们假设，基于挑衅性的新数据，大脑的先天免疫系统在成功衰老和抵抗AD中起着核心作用。先天免疫系统在衰老和AD中的作用已经得到有限的研究，并且知之甚少。这在一定程度上是由于人们对小胶质细胞及其与外周免疫系统的关系感到困惑。我们发现了小鼠和人类大脑中常驻小胶质细胞与招募的单核细胞的独特生物标志物和microRNA/基因特征。这一进展为确定先天免疫细胞在大脑衰老和AD发展中的功能和功能障碍提供了独特的机会。待检验的假设：我们假设先天免疫系统随年龄的变化在影响人类大脑的衰老疾病（包括AD）的发展中起着重要作用。我们称之为“大脑老化的先天免疫假说”。“如果我们的假设是正确的，它将改变我们对健康衰老和AD中microgli和巨噬细胞功能的理解，并通过靶向这些独特的细胞群提供治疗AD的新治疗机会。我们已经建立了一个全面的研究策略，在动物模型和老年人受试者中测试我们假设的关键组成部分。目标1.研究衰老和AD小鼠模型中的常驻小胶质细胞/募集的巨噬细胞。使用我们独特的标志物，区分居民小胶质细胞浸润单核细胞，我们将确定这两个人口在老化和AD进展的基因/microRNA谱，并研究它们与A？低聚物目标二。靶向小胶质细胞和募集的单核细胞作为动物模型中AD的治疗。我们将靶向先天免疫系统的细胞来治疗AD的动物模型，基于我们对这些细胞的表征。我们将利用我们独特的小胶质细胞/单核细胞抗体，独特的microRNA的antigomirs和TAM系统的配体。目标3。研究人类衰老和AD患者大脑中的小胶质细胞和单核细胞.我们将研究两个独特的人类群体。1.我们将与大卫班尼特（拉什记忆和衰老项目）合作，研究来自衰老大脑队列的病理标本。我们将对健康老年人大脑和典型AD患者大脑中的小胶质细胞和募集的单核细胞进行免疫病理学表征，并将小胶质细胞的变化与衰老中发生的变化相关联。2.我们将调查A？在老年人群的脑中的沉积（通过PiB成像测量）和外周血中的先天免疫系统中，我们将对正在进行PiB成像和认知评估的老龄队列（由Brigham and Women's Hospital的Reisa Sperling博士进行NIH研究）的血液中的单核细胞进行表征。这将提供外周先天免疫系统和大脑随年龄变化之间的直接联系。

DESCRIPTION (provided by applicant): A major health problem relates to progressive cognitive decline with age and the threat of Alzheimer's disease (AD). We postulate, based on provocative new data, that the brain's innate immune system plays a central role in successful aging and resistance to AD. The role of the innate immune system in aging and AD has received limited study and is poorly understood. This is due in part to confusion regarding microglial cells and how they relate to the peripheral inate immune system. We discovered unique biomarkers and microRNA/gene signatures for resident microglia in the brain vs. recruited monocytes in both mice and humans. This advance presents a unique opportunity to determine the functions and dysfunctions of innate immune cells in brain aging and the development of AD. Hypothesis to be tested: We hypothesize that changes in the innate immune system with age play a major role in the development of diseases of aging that affect the human brain, including AD. We have termed this the "Innate immunity hypothesis of brain aging." If our hypothesis is correct, it will change our understanding of the functions of microgli and macrophages in healthy aging and in AD and provide new therapeutic opportunities to treat AD by targeting these unique cell populations. We have established a comprehensive research strategy to test the key components of our hypothesis both in animal models and in aging human subjects. Aim 1. Investigate resident microglia/recruited macrophages in aging and AD mouse models. Using our unique markers that distinguish resident microglia from infiltrating monocytes, we will determine the gene/microRNA profiles of these two populations during aging and AD progression and study their interaction with A? oligomers. Aim 2. Target microglia and recruited monocytes as a treatment for AD in animal models. We will target cells of the innate immune system to treat animal models of AD based on our characterization of these cells. We will utilize our unique antibodies to microglia/ monocytes, antigomirs to unique microRNAs, and ligands of the TAM system. Aim 3. Investigate brain- resident microglia and monocytes during human aging and in AD. We will study two unique human cohorts. 1. We will investigate pathologic specimens from an aging brain cohort in collaboration with David Bennett (Rush Memory and Aging Project). We will perform immunopathological characterization of microglia and recruited monocytes in healthy aged brains and those with typical AD and correlate changes in microglia with changes that occur in aging. 2. We will investigate the relationship between A? deposition in the brains of an aging human population (measured by PiB imaging) and the innate immune system in the peripheral blood. We will characterize monocytes in the blood from an aging cohort (under NIH study by Dr. Reisa Sperling at Brigham and Women's Hospital) in whom PiB imaging and cognitive assessment is being performed. This will provide a direct link between the peripheral innate immune system and brain changes with aging.