Role of Senescent T cells in Alzheimer's Disease

衰老 T 细胞在阿尔茨海默病中的作用

• 批准号: 9975395
• 负责人: Guangyong Peng
• 金额: $ 28.59万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-02-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975395
• 关键词: ATM Signaling Pathway; Address; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Area; Binding; CD8-Positive T-Lymphocytes; Caregivers; Cell Aging; Cell physiology; Cells; Cellular Structures; DNA Damage; Dementia; Development; Diagnostic; Distress; Goals; Hippocampus (Brain); Human; Immune; Immune system; Immunotherapy; Inflammatory; Knowledge; Lead; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Mediating; Metabolic; Metabolism; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome Study; Pathogenesis; Pathologic Processes; Patients; Phenotype; Population; Prevention therapy; Public Health; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Structure of choroid plexus; T-Lymphocyte; Testing; Therapeutic; Treatment Efficacy; Undifferentiated; age related; base; cytokine; effector T cell; exhaust; improved; in vivo; insight; mouse model; nervous system disorder; neuronal metabolism; novel; novel strategies; peripheral blood; prevent; response; senescence; tau Proteins

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia, and also an age-related neurological disorder. AD not only causes severe distress for patients and caregivers, but it also becomes a major public health predicament. However, the mechanisms responsible for the pathogenesis of AD are still unclear, which is a major challenge for AD prevention and therapy. Increasing evidence suggests that dysfunctional and aging immune system may be a primary factor/inducer for the development of AD. Accumulated regulatory T (Treg) cells and senescent T cells have been identified in AD patients, but the functional roles of these T cell populations in the pathogenesis of AD are poorly understood. Furthermore, the causative relationship between Treg and senescent T cells in AD development and progression is unknown. We recently discovered a novel suppressive mechanism that human Treg cells can induce responder naïve and effector T cell senescence. Importantly, our more recent studies demonstrated that senescent T cells can promote the aggregation of amyloid precursor protein (APP), amyloid beta (Aβ) and Tau proteins in human neuronal cells. Therefore, an improved understanding of the molecular and cellular processes of senescent T cells in the pathogenesis of AD is urgently needed, which could lead to the development of novel and effective therapeutic strategies. The central hypotheses of this proposal are: 1) accumulated Treg cells induce senescence among T cells thereby promoting the development and pathogenesis of AD; 2) blockage of senescence in T cells is a critical checkpoint to control AD pathologic processes and progression, which will provide a novel strategy for AD prevention and immunotherapy. Specific Aim 1 seeks to determine whether senescent T cells induced by Treg cells are a critical player for the pathogenesis of AD in vivo in animal models. Aim 2 will first investigate whether and how senescent T cells reprogram the metabolism and functions of differentiated and undifferentiated neuronal cells. We will then identify the unique senescence-associated secretory phenotype (SASP) of senescent T cells, including inflammatory cytokines and metabolites, responsible for the functional changes in neurons induced by senescent T cells, resulting in neurodegeneration and AD development. Aim 3 will further propose complementary in vivo studies to test our hypothesis and the novel concept that reversal of T cell senescence through the inhibition of ATM signaling and/or MAPK signaling can prevent AD development and mitigate AD pathology in a spontaneous senescence accelerated mouse model. A positive outcome of these studies should lead to novel strategies for molecular control of T cell fate and function for AD prevention and immunotherapy.

项目摘要/摘要 阿尔茨海默病(AD)是导致痴呆的最常见原因，也是一种与年龄相关的神经系统疾病 无序。AD不仅给患者和照顾者带来了严重的痛苦，而且也成为了主要的公众 健康困境。然而，阿尔茨海默病的发病机制尚不清楚。 是AD预防和治疗的一大挑战。越来越多的证据表明，功能失调和衰老 免疫系统可能是AD发生发展的主要因素/诱因。累积调节T(Treg) 已经在AD患者中发现了细胞和衰老的T细胞，但这些T细胞的功能 人们对AD发病机制知之甚少。此外，两者之间的因果关系 Treg和衰老的T细胞在AD的发生发展中的作用尚不清楚。我们最近发现了一本小说 人Treg细胞诱导应答者幼稚和效应T细胞衰老的抑制机制。 重要的是，我们最近的研究表明，衰老的T细胞可以促进 人类神经细胞中的淀粉样前体蛋白(APP)、淀粉样β蛋白(Aβ)和Tau蛋白。因此，一个 更深入地了解衰老T细胞在糖尿病发病机制中的分子和细胞过程 AD是迫切需要的，它可以导致新的有效的治疗策略的发展。这个 这一建议的中心假设是：1)积累的Treg细胞导致T细胞之间的衰老 促进AD的发展和发病；2)阻断T细胞的衰老是关键 Checkpoint控制AD的病理过程和进展，这将为AD提供一种新的策略 预防和免疫治疗。特定目标1试图确定Treg诱导的衰老T细胞 在动物模型中，细胞在阿尔茨海默病的发病机制中起关键作用。目标2将首先调查 衰老的T细胞是否以及如何重新编程分化的和 未分化的神经细胞。然后我们将鉴定与衰老相关的独特的分泌表型 衰老T细胞(SASP)，包括炎性细胞因子和代谢产物，负责功能性 衰老的T细胞引起神经元的变化，导致神经退行性变和AD的发展。目标3 将进一步提出补充的体内研究，以测试我们的假设和新的概念，逆转 通过抑制ATM信号和/或MAPK信号抑制T细胞衰老可以阻止AD的发生 并减轻自发性衰老加速小鼠模型中的AD病理。一个积极的结果 这些研究将导致分子控制T细胞命运和功能的新策略，以预防AD 和免疫疗法。