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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目概要/摘要阿尔茨海默病（AD）是痴呆症最常见的原因，也是一种与年龄相关的神经系统疾病 AD 疾病不仅给患者和护理人员带来严重的痛苦，而且还成为一个主要的公众问题。然而，AD 的发病机制仍不清楚。越来越多的证据表明功能失调和衰老是 AD 预防和治疗的主要挑战。免疫系统可能是 AD 发生的主要因素/诱导因素。 AD 患者中已鉴定出 T 细胞和衰老 T 细胞，但这些 T 细胞的功能作用此外，人们对 AD 发病机制之间的因果关系知之甚少。 Tregs 和衰老 T 细胞在 AD 发生和进展中的作用尚不清楚。人类 Treg 细胞对诱导剂幼稚和效应 T 细胞衰老作出反应的抑制机制。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元细胞中的淀粉样前体蛋白 (APP)、淀粉样β (Aβ) 和 Tau 蛋白。提高了对衰老 T 细胞在疾病发病机制中的分子和细胞过程的了解 AD 是迫切需要的，这可能会导致新型有效的治疗策略的开发。该提案的中心假设是：1）积累的Treg细胞诱导T细胞衰老，从而导致T细胞衰老。促进AD的发展和发病机制；2）阻止T细胞衰老是关键检查点控制AD病理过程和进展，这将为AD提供新的策略具体目标 1 旨在确定 Treg 是否诱导衰老 T 细胞。 Aim 2 将首先在动物模型中研究细胞是 AD 体内发病机制的关键因素。衰老 T 细胞是否以及如何重新编程分化和分化细胞的代谢和功能然后我们将鉴定出与衰老相关的独特的分泌表型。衰老 T 细胞（SASP），包括炎症细胞因子和代谢物，负责功能性衰老 T 细胞诱导神经元发生变化，导致神经变性和 AD 发展。将进一步提出补充的体内研究来检验我们的假设和逆转的新概念通过抑制 ATM 信号和/或 MAPK 信号传导的 T 细胞衰老可以预防 AD 发展并减轻自发衰老加速小鼠模型中的 AD 病理学结果。这些研究应该会产生分子控制 T 细胞命运和功能以预防 AD 的新策略和免疫疗法。