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

阿尔茨海默病发病机制和免疫治疗中 T 细胞衰老的代谢控制

• 批准号: 10830669
• 负责人: Guangyong Peng
• 金额: $ 38.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10830669
• 关键词: ATM Signaling Pathway; Acceleration; Address; Affect; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Area; Binding; CD8-Positive T-Lymphocytes; Caregivers; Cell Aging; Cell physiology; Cells; Cellular Structures; DNA Damage; Dementia; Development; Diagnostic; Disease Progression; Distress; Enzymes; Etiology; Exhibits; Functional disorder; Goals; Human; Immune; Immune system; Immunotherapy; Knowledge; Lipids; MAP Kinase Gene; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Onset of illness; Outcome Study; Pathogenesis; Pathologic Processes; Patients; Phenotype; Population; Process; Public Health; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Up-Regulation; Writing; adaptive immunity; age related; aged; disorder control; effector T cell; improved; in vivo; lipid metabolism; mouse model; nervous system disorder; novel; novel strategies; p38 Mitogen Activated Protein Kinase; peripheral blood; prevent; programs; response; senescence; tau Proteins; therapeutically effective

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.

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。累积衰老T细胞 在AD患者和老年AD发病小鼠中均已发现， 增加的衰老T细胞和AD的发展和进展是未知的。我们最近发现了一个 人Treg细胞可诱导应答者幼稚和效应T细胞的新抑制机制 衰老衰老的T细胞表现出活跃的脂质代谢，并具有独特的衰老相关的细胞因子。 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， 淀粉样蛋白β（Aβ）和Tau蛋白在人类神经元细胞中的作用。因此，更好地了解 目前迫切需要研究衰老T细胞在AD发病机制中的分子和细胞过程， 可能会导致新的和有效的治疗策略的发展。这个问题的核心假设是 建议是：1）积累的衰老T细胞与过度的脂质代谢促进发育， AD的发病机制; 2）通过脂质重编程阻断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，这将为AD的预防和治疗提供一种新的策略， 免疫疗法。具体目标1旨在确定衰老T细胞是否伴有脂质代谢紊乱 是AD发病机制的关键驱动因素。我们将剖析分泌脂质的致病作用 衰老T细胞的代谢物在神经元细胞的重编程功能中的作用。我们还将确定 衰老T诱导的神经元功能变化的分子和代谢信号 细胞，导致神经变性和AD发展。具体目标2将提出补充体内 研究以确定累积的衰老T细胞和AD发展之间的因果关系 和自发性衰老加速的SAMP 8小鼠模型中的疾病进展。然后我们将测试 我们的假设和新的概念，即重新编程T细胞脂质代谢，以逆转T细胞 衰老是预防AD发展和增强AD免疫治疗功效的一种新策略。一 这些研究的积极结果应该会导致T细胞命运的代谢控制的新策略， 用于AD预防和免疫治疗。