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与随年龄增长的渐进性认知能力下降和阿尔茨海默病(AD)的威胁有关。基于具有挑衅性的新数据，我们假设大脑的先天免疫系统在成功衰老和抵抗AD方面发挥着核心作用。先天免疫系统在衰老和阿尔茨海默病中的作用一直受到有限的研究，而且知之甚少。这在一定程度上是由于对小胶质细胞及其与外周免疫系统的关系的混淆。我们在小鼠和人类中发现了驻留在大脑中的小胶质细胞与招募的单核细胞之间的独特生物标志物和microRNA/基因签名。这一进展为确定先天免疫细胞在脑老化和阿尔茨海默病发展中的功能和功能障碍提供了一个独特的机会。有待检验的假设：我们假设，随着年龄的增长，先天免疫系统的变化在影响人类大脑的衰老疾病的发展中发挥着主要作用，包括阿尔茨海默病。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，它将改变我们对微胶细胞和巨噬细胞在健康衰老和AD中功能的理解，并通过靶向这些独特的细胞群为治疗AD提供新的治疗机会。我们已经建立了一个全面的研究策略，在动物模型和老龄化的人类受试者中测试我们假说的关键组成部分。目的1.研究衰老和AD小鼠模型中滞留的小胶质细胞/募集的巨噬细胞。使用我们独特的标记区分驻留的小胶质细胞和渗透的单核细胞，我们将确定这两个群体在衰老和AD进展过程中的基因/microRNA谱，并研究它们与A？齐聚物。目的2.靶向小胶质细胞和募集单核细胞作为治疗AD动物模型的方法。我们将以先天免疫系统的细胞为靶点，根据我们对这些细胞的特征来治疗AD的动物模型。我们将利用我们独特的小胶质细胞/单核细胞抗体、独特microRNAs的抗原体和系统的配体。目的3.研究人类衰老和阿尔茨海默病(AD)时脑内驻留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David Bennett(Rush Memory And Aging Project)合作，研究一个老化脑队列的病理标本。我们将对健康老年人和典型阿尔茨海默病患者的小胶质细胞和招募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过程中发生的变化联系起来。2.我们将调查A？老龄化人群大脑中的沉积(通过PIB成像测量)和外周血液中的先天免疫系统。我们将从一个正在进行PIB成像和认知评估的老年队列(由布里格姆妇女医院的Reisa Sperling博士进行的NIH研究)中确定血液中单核细胞的特征。这将在外周先天免疫系统和大脑随年龄增长的变化之间提供直接联系。 与公共健康相关：随着年龄的增长，大脑功能下降，导致认知能力下降，在某些情况下还会导致阿尔茨海默病(AD)。我们推测先天免疫系统在AD的衰老和发展中起主要作用。我们将研究这种关系，以开发预防阿尔茨海默病和认知功能衰退的治疗方法。

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. PUBLIC HEALTH RELEVANCE: There is decrease in brain function with aging that leads to cognitive decline and in some instances Alzheimer's Disease (AD). We hypothesize that the innate immune system plays a major role in aging and the development of AD. We will study this relationship to develop treatments to prevent AD and cognitive decline with aging.