Role of Senescent T cells in Alzheimer's Disease

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是痴呆症最常见的病因，也是一种与年龄相关的神经系统疾病 disorder. AD不仅给患者和护理者带来严重的痛苦，而且也成为一个主要的公共卫生问题。 健康困境然而，AD发病机制尚不清楚， 是AD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AD发生发展的主要因素/诱导物。累积调节性T细胞（Treg） 在AD患者中已经发现了T细胞和衰老T细胞，但是这些T细胞的功能作用是不稳定的。 人群在AD发病机制中的作用知之甚少。此外，因果关系 Treg和衰老T细胞在AD发生和进展中的作用尚不清楚。我们最近发现了一本小说 人Treg细胞可以诱导应答者幼稚和效应T细胞衰老的抑制机制。 更重要的是，我们最近的研究表明，衰老的T细胞可以促进聚集， 淀粉样蛋白前体蛋白（APP）、淀粉样蛋白β（Aβ）和Tau蛋白。所以一间 提高了对衰老T细胞的分子和细胞过程的理解， AD是迫切需要的，这可能导致新的和有效的治疗策略的发展。的 该提议的中心假设是：1）累积的Treg细胞诱导T细胞之间的衰老，从而 促进AD的发展和发病机制; 2）阻断T细胞衰老是关键的 检测点控制AD的病理过程和进展，为AD的治疗提供了新的策略 预防和免疫治疗。具体目标1旨在确定Treg诱导的衰老T细胞是否 细胞是动物模型中AD体内发病的关键因素。Aim 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T细胞的代谢和功能， 未分化的神经细胞然后我们将确定独特的衰老相关的分泌表型 衰老T细胞的SASP，包括炎性细胞因子和代谢物，负责功能性免疫应答。 衰老T细胞诱导的神经元变化，导致神经变性和AD发展。目标3 将进一步提出补充体内研究，以测试我们的假设和新的概念，逆转的 通过抑制ATM信号和/或MAPK信号使T细胞衰老可以防止AD的发展 并减轻自发性衰老加速小鼠模型中的AD病理。取得积极成果 这些研究将为AD的预防提供T细胞命运和功能的分子控制的新策略 和免疫疗法。

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.