Studying the impact of altered CD8+ T cell immunity in Alzheimer's disease

项目摘要。阿尔茨海默病（AD）是一种慢性进行性神经退行性疾病， 占所有痴呆症病例的60-70%。遗传学研究报告了淀粉样蛋白可能的致病作用- 淀粉样前体蛋白（APP）衍生的β淀粉样蛋白（Aβ）在AD的发生发展中起重要作用。的 Aβ肽在脑内的积累可启动AD的病理生理学，导致神经系统损害， 缠结和神经变性。临床前和尸检研究表明， 炎症途径和AD病理学发展之间的联系。然而，以前的研究 主要集中在先天免疫细胞上。免疫系统的改变，包括T细胞，随着年龄的增长而发生， 很可能导致感染和恶性肿瘤的发生。在人类T细胞中，可能是最多的 随着年龄的增长，一个显著的变化是外周血中记忆性CD 8 + T细胞的扩增，尽管CD 4 + T细胞的变化是在外周血中记忆性CD 8 + T细胞的扩增。 也报道了T细胞亚群。我们发现人类效应记忆（EM， CCR 7-CD 45 RA +/-）表达低水平IL-7受体α（IL-7 R α低）的CD 8 + T细胞，其具有明显的 这些特征包括效应分子、转录因子和DNA甲基化谱。最近我们 研究了这种与年龄相关的IL-7 R α低EM CD 8 + T细胞扩增与 人外周血细胞的总体转录组学谱。交叉差异表达基因 在IL-7 R α低EM CD 8 + T细胞中对来自人外周血的年龄相关基因的DEG的研究显示， IL-7 R α低EM CD 8 + T细胞的年龄相关基因表达特征，对应于15%的 年龄相关基因（244/1，497），由一项对来自以下人群的人外周全血的荟萃分析研究报告： 约15，000人。最近的一项研究报道了CD 45 RA + EM CD 8 + T细胞在小鼠中的扩增。 患有痴呆或轻度认知障碍（MCI）的患者的外周血和脑脊液， AD，与认知相关。重要的是，这些细胞大多是IL-7 R α（CD 127）低水平细胞。因此，我们将 研究AD患者IL-7 R α低水平细胞年龄相关性扩增的可能意义， AD患者IL-7 R α低EM CD 8 + T细胞基因标记水平升高， 这些细胞在外周血中的扩增，与AD严重程度和脑突触的测量相关。 密度的该提案的目的是检验假设，目标如下：1）目标1。阐明了 AD患者外周血中IL-7 R α低EM CD 8 + T细胞基因签名水平升高， 与疾病严重程度和脑突触密度相关;和2）Aim 2.说明AD患者有 与疾病严重程度和脑突触密度相关的改变的T细胞谱。总体而言，我们的补充 该提案是独特的和重要的，因为它对CD 8 + T细胞的作用进行了深入研究，特别是IL- 7 R α低EM细胞，在AD中，这开辟了健康老龄化和AD研究的新领域。

Project Summary. Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder that accounts for 60-70% of all cases of dementia. Genetic studies reported the possible causative role of amyloid- β (Aβ), which is derived from the amyloid precursor protein (APP), in the development of AD. The accumulation of Aβ peptides in the brain can initiate the pathophysiology of AD, leading to neurofibrillary tangles and neurodegeneration. Preclinical and postmortem studies demonstrate a significant association between inflammatory pathways and the development of AD pathology. However, previous studies have focused mostly on innate immune cells. Alterations in the immune system, including T cells, occur with aging, likely contributing to the development of infections and malignancies. In human T cells, probably the most prominent change with aging is memory CD8+ T cell expansion in peripheral blood although alterations in CD4+ T cell subsets are reported as well. We found the age-associated expansion of human effector memory (EM, CCR7-CD45RA+/-) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) which have distinct characteristics including effector molecules, transcription factors, and DNA methylation profiles. Recently, we investigated the possible relationship of this age-associated expansion of IL-7Rαlow EM CD8+ T cells with the global transcriptomic profile of peripheral blood cells in humans. Crossing differentially expressed genes (DEGs) in IL-7Rαlow EM CD8+ T cells against age-associated genes from human peripheral blood revealed an age-associated gene expression signature of the IL-7Rαlow EM CD8+ T cells that corresponded to 15% of the age-associated genes (244/1,497) reported by a meta-analysis study on human peripheral whole blood from approximately 15,000 individuals. A recent study reported the expansion of CD45RA+ EM CD8+ T cells in peripheral blood and cerebrospinal fluids of patients with dementia or mild cognitive impairment (MCI) due to AD, correlating with cognition. Importantly, such cells are mostly IL-7Rα(CD127)low cells. Thus, we will investigate the possible implication of the age-associated expansion of IL-7Rαlow cells in AD based on the hypothesis that patients with AD have increased levels of IL-7Rαlow EM CD8+ T cell gene signature and an expansion of these cells in peripheral blood, correlating with measures of AD severity and brain synaptic density. The goal of the proposal is to test the hypothesis with the following aims: 1) Aim 1. Elucidate that patients with AD have increased levels of IL-7Rαlow EM CD8+ T cell gene signature in peripheral blood which correlate with disease severity and brain synaptic density; and 2) Aim 2. Elucidate that patients with AD have an altered T cell profile correlating with disease severity and brain synaptic density. Overall, our supplement proposal is unique and significant since it conducts in-depth studies on the role of CD8+ T cells, especially IL- 7Rαlow EM cells, in AD, which opens a new area of research in both healthy aging and AD.