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 阿尔茨海默氏病（AD）是痴呆症的最常见原因，也是与年龄有关的神经系统 紊乱。广告不仅会给患者和看护人带来严重的困扰，而且也成为主要的公众 健康预测。但是，导致AD发病机理的机制仍不清楚，这是 是预防和治疗的主要挑战。越来越多的证据表明功能失调和衰老 免疫系统可能是开发AD的主要因素/诱导剂。累积的调节t（Treg） 在AD患者中已经鉴定出细胞和感觉T细胞，但是这些T细胞的功能作用 广告发病机理中的种群了解不足。此外， Treg和Sensent T细胞在AD发育和进展中尚不清楚。我们最近发现了一本小说 抑制性机制，即人treg细胞可以诱导呼吸器幼稚和效应T细胞感应。 重要的是，我们最近的研究表明，感觉T细胞可以促进 人神经元细胞中的淀粉样蛋白前体蛋白（APP），淀粉样蛋白β（Aβ）和tau蛋白。因此，一个 在对感官T细胞的分子和细胞过程中的理解中有了改进的理解 迫切需要广告，这可能导致新颖有效的治疗策略的发展。 该提案的中心假设是：1）累积的Treg细胞在T细胞之间诱导感受 促进AD的发育和发病机理； 2）T细胞中的感应阻塞是关键 控制AD病理过程和进展的检查站，这将为AD提供新的策略 预防和免疫疗法。特定的目标1试图确定是否由Treg诱导的感觉T细胞 细胞是动物模型中AD体内发病机理的关键参与者。 AIM 2将首先调查 感官T细胞是否以及如何重新编程分化和分化和功能的功能 未分化的神经元细胞。然后，我们将确定与独特的感应相关的秘书表型 感觉T细胞的（SASP），包括炎性细胞因子和代谢产物，负责功能 感官T细胞诱导的神经元的变化，导致神经退行性变化和AD发育。目标3 将进一步建议在体内研究中完成，以检验我们的假设和逆转的新颖概念 通过抑制ATM信号传导和/或MAPK信号传导T细胞感应 并减轻赞助感应加速的小鼠模型中的AD病理。积极的结果 这些研究应导致对T细胞命运和AD预防功能的分子控制的新策略 和免疫疗法。