Metabolic Control of T Cell Senescence in Pathogenesis and Immunotherapy of Alzheimer's Disease

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。蓄积的衰老T细胞 在AD患者和老年AD发病小鼠中都已被发现，但两者之间的致病关系 衰老T细胞的增多和AD的发生发展尚不清楚。我们最近发现了一种 人Treg细胞诱导反应性幼稚T细胞和效应T细胞的新抑制机制 衰老。衰老的T细胞表现出活跃的脂代谢，并具有独特的衰老相关 分泌表型(SASP)，产生大量的脂质和代谢物。重要的是，我们最近 研究表明，衰老的T细胞可以促进淀粉样前体蛋白(APP)的聚集， 人类神经细胞中的淀粉样β蛋白(Aβ)和Tau蛋白。因此，更好地理解 衰老T细胞在AD发病机制中的分子和细胞过程是迫切需要的 可能导致开发新的有效的治疗策略。这其中的中心假设是 建议：1)蓄积衰老的T细胞，脂肪代谢过度，促进发育和 阿尔茨海默病的发病机制；以及2)通过脂质重编程阻止T细胞衰老是一个关键的检查点 控制AD的病理过程和进展，将为AD的预防和治疗提供新的策略 免疫疗法。特定目标1试图确定衰老的T细胞是否存在脂代谢障碍 是阿尔茨海默病发病的关键驱动因素。我们将剖析分泌型脂类的致病作用。 衰老T细胞代谢产物在神经细胞重编程功能中的作用。我们还将确定 衰老T细胞引起神经元功能改变的分子和代谢信号 细胞，导致神经退化和阿尔茨海默病的发展。特定目标2将在体内提出补充方案 衰老T细胞蓄积与阿尔茨海默病发病关系研究 以及在自发衰老加速的SAMP8小鼠模型中的疾病进展。然后我们将测试 我们的假设和T细胞脂代谢的重新编程以逆转T细胞的新概念 衰老是预防AD发生和提高AD免疫治疗疗效的一种新策略。一个 这些研究的积极结果应该导致T细胞命运代谢控制的新策略和 具有预防AD和免疫治疗的作用。

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 senescent T cells have been identified in both AD patients and in aged AD onset mice, but the causative relationship between the increased senescent T cells and 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. Senescent T cells exhibit active lipid metabolism and possess a unique senescence-associated secretory phenotype (SASP), producing high amounts of lipids and metabolites. 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 senescent T cells with excessive lipid metabolism promote the development and pathogenesis of AD; and 2) blockage of senescence in T cells via lipid reprogramming 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 with lipid metabolism disorder are a critical driver for the pathogenesis of AD. We will dissect the causative role of the secretory lipid metabolites of senescent T cells in reprogramming functions of neuronal cells. We will also identify the molecular and metabolic signaling responsible for the functional changes in neurons induced by senescent T cells, resulting in neurodegeneration and AD development. Specific Aim 2 will propose complementary in vivo studies to identify the causative relationship between the accumulated senescent T cells and AD development and disease progression in a spontaneous senescence accelerated SAMP8 mouse model. We will then test our hypothesis and the novel concept that that reprogramming of T cell lipid metabolism to reverse T cell senescence is a novel strategy to prevent AD development and enhance efficacy for AD immunotherapy. A positive outcome of these studies should lead to novel strategies for metabolic control of T cell fate and function for AD prevention and immunotherapy.