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

研究 CD8 T 细胞免疫改变对阿尔茨海默病的影响

基本信息

批准号：
10119925
负责人：
Insoo Kang
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10119925
关键词：
2 year old Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid beta-Protein Amyloid beta-Protein Precursor Area Autoimmunity Autopsy Biological Blood Blood Cells Blood specimen Brain CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Cerebrospinal Fluid Characteristics Chronic Clinical Clinical Assessment Tool Clinical Data Cognition Communicable Diseases Cytometry DNA Methylation Dementia Development Disease Disease Progression Elderly Etiology Flow Cytometry Frequencies Functional disorder Gender Gene Expression Profile Genes Genetic study Goals Human IL7R gene Immune Immune system Immunity Immunization Individual Infection Inflammaging Inflammation Inflammatory Innate Immune System Interleukin 7 Receptor Interleukin-6 Letters Link Malignant Neoplasms Measures Memory Meta-Analysis Methods Microglia Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Participant Pathologic Pathway interactions Patients Peripheral Positron-Emission Tomography Reporting Research Role Severities Severity of illness Synapses T-Lymphocyte T-Lymphocyte Subsets TNF gene Technology Testing Time Tracer Visit Whole Blood Work abeta accumulation aging gene base cell dimension cohort cytokine density differential expression follow-up genetic signature healthy aging high dimensionality mild cognitive impairment molecular imaging nano-string neuroinflammation novel strategies peripheral blood pre-clinical recruit single cell analysis transcription factor transcriptomics

项目摘要

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.

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。占所有痴呆病例的 60-70%。遗传学研究报告称，淀粉样蛋白可能是致病因素。 β (Aβ) 源自淀粉样前体蛋白 (APP)，参与 AD 的发展。 Aβ肽在大脑中的积累可以启动AD的病理生理学，导致神经原纤维临床前和尸检研究表明缠结和神经退行性变之间存在显着关联。然而，之前的研究已经揭示了炎症途径与 AD 病理学发展之间的关系。主要关注先天免疫细胞，包括 T 细胞，随着衰老而发生变化，在人类 T 细胞中，可能是导致感染和恶性肿瘤发生的最重要因素。随年龄增长的显着变化是记忆 CD8+，尽管外周血中 T 细胞扩增 CD4+ 发生变化我们还发现了 T 细胞亚群与年龄相关的人类效应记忆（EM、 CCR7-CD45RA+/-) CD8+ T 细胞表达低水平的 IL-7 受体 α (IL-7Rαlow)，具有明显的最近，我们研究了包括效应分子、转录因子和 DNA 甲基化谱在内的特征。研究了 IL-7Rαlow EM CD8+ T 细胞与年龄相关的扩张与人类外周血细胞的总体转录组谱。 IL-7Rαlow EM CD8+ T 细胞针对人外周血中年龄相关基因的（DEG）揭示了 IL-7Rαlow EM CD8+ T 细胞的年龄相关基因表达特征，相当于 15% 对人外周全血进行荟萃分析研究报告的年龄相关基因 (244/1,497) 最近的一项研究报告了大约 15,000 人体内 CD45RA+ EM CD8+ T 细胞的扩增。痴呆或轻度认知障碍（MCI）患者的外周血和脑脊液 AD，与认知相关，重要的是，此类细胞大多是 IL-7Rα(CD127) 低的细胞。研究 AD 中 IL-7Rαlow 细胞与年龄相关的扩增的可能含义假设 AD 患者的 IL-7Rαlow EM CD8+ T 细胞基因特征水平升高，并且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该提案的目标是测试假设，其目标如下： 1) 目标 1. 阐明这一点。 AD 患者外周血中 IL-7Rαlow EM CD8+ T 细胞基因特征水平升高， 2) 目标 2. 阐明 AD 患者总体而言，我们的补充剂与疾病严重程度和大脑突触密度相关。该提案对CD8+ T细胞，特别是IL-的作用进行了深入研究，具有独特性和重要意义。 7Rαlow EM 细胞在 AD 中的应用，开辟了健康衰老和 AD 的新研究领域。