The role of brain resident T cells in Alzheimer's disease

大脑常驻 T 细胞在阿尔茨海默病中的作用

• 批准号: 10515916
• 负责人: Pamela Rosato
• 金额: $ 65.8万
• 依托单位: DARTMOUTH COLLEGE
• 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515916
• 关键词: 3xTg-AD mouse; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Antigens; Area; Atlases; Automobile Driving; Autopsy; Biology; Brain; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cerebrospinal Fluid; Clonality; Cognition; Collaborations; Complement; Conflict (Psychology); Data; Deposition; Development; Disease; Disease Outcome; Disease Progression; Flow Cytometry; Foundations; Goals; Histologic; Human; Immune; Immunologic Surveillance; Immunologic Techniques; Immunotherapy; Impaired cognition; Individual; Knock-out; Knowledge; Longitudinal Studies; Macrophage Activation; Mediating; Memory; Microglia; Modeling; Multiple Sclerosis; Mus; Natural Killer Cells; Nerve Degeneration; Neuroimmune; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Phagocytosis; Phenotype; Play; Population; Positioning Attribute; Proteins; Reporting; Research; Role; Synapses; T cell clonality; T cell receptor repertoire sequencing; T memory cell; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Testing; Tissues; base; behavior test; brain shape; brain tissue; cell motility; experimental study; extracellular; familial Alzheimer disease; immune activation; improved; innovation; insight; macrophage; migration; mouse model; nervous system disorder; neuroinflammation; neuropathology; new therapeutic target; novel; protein aggregation; recruit; response; single-cell RNA sequencing; tau Proteins; translational study

PROJECT SUMMARY/ABSTRACT T cells were first observed in postmortem brains of Alzheimer’s disease (AD) patients decades ago, yet very little is known about their role in disease progression. AD is marked by oligomerization of specific proteins that can accumulate into extracellular plaques, driving research to understand innate immune cells in AD due to their potential for reacting to and clearing these plaques. More recent evidence suggests that adaptive immune cells play a significant role in AD; numbers of CD8+ T cells are significantly increased in AD brains, and expansion of a subset of memory CD8+ T cells in the cerebrospinal fluid of AD patients is negatively associated with cognition. To date, T cell depletion and knock-out studies in mice have yielded conflicting data on the influence of T cells in AD. However, a population of T cells that has long been overlooked due to their only recent discovery and the historic view of the brain as immune privilege are tissue resident memory T cells (TRM), which reside in the brain and are optimally positioned to exert local immune activation. As there is currently no defined T cell antigen in Alzheimer’s disease, we will take an innovative approach to model TRM activation in the brain using a model antigen. This will be the first study to examine TRM in context of Alzheimer’s disease and to examine the impact of T cell activation in a defined manner on AD progression. The objectives of this proposal are to i) test the ability of brain CD8+ TRM to trigger innate immune cell activation, including NK cells, microglia and macrophages, in a mouse model of AD, ii) determine the impact of brain CD8+ TRM activation on Alzheimer’s disease progression in mice, including cognition and pathology, and iii) determine the migration dynamics, abundance and clonality of CD8+ TRM in mouse and human AD brain. These goals will be attained by complementing classical immunologic techniques for studying TRM in mouse models with a continuing collaboration with onsite neuropathologists to study T cells from human postmortem tissue from AD and non-neurologically involved brain tissue at a single cell level. Collectively, these experiments will enhance our understanding of the role of CD8+ TRM in Alzheimer’s disease and has potential to provide insight into T cell functions in other neurological diseases, reveal novel therapeutic targets, and overall build a foundational understanding of TRM functions in the brain.

项目概要/摘要 几十年前，人们首次在阿尔茨海默病 (AD) 患者死后大脑中观察到 T 细胞，但数量很少 众所周知，它们在 AD 疾病进展中的作用以特定蛋白质的寡聚化为标志。 积累成细胞外斑块，推动研究了解 AD 中的先天免疫细胞，因为它们 最近的证据表明，适应性免疫细胞具有对这些斑块做出反应并清除这些斑块的潜力。 在 AD 中发挥重要作用；AD 大脑中 CD8+ T 细胞的数量显着增加，并且 AD 患者脑脊液中的记忆 CD8+ T 细胞亚群与认知呈负相关。 迄今为止，针对小鼠的 T 细胞耗竭和敲除研究得出了关于 T 细胞影响的相互矛盾的数据 然而，在 AD 中，由于最近才发现的 T 细胞群体长期以来一直被忽视。 大脑作为免疫特权的历史观点是驻留在大脑中的组织驻留记忆 T 细胞 (TRM) 由于目前尚无明确的 T 细胞抗原，因此处于最佳位置以发挥局部免疫激活作用。 阿尔茨海默病，我们将采用创新方法，使用模型来模拟大脑中的 TRM 激活 这将是第一项在阿尔茨海默病背景下检查 TRM 并检查其影响的研究。 该提案的目的是：i) 测试 T 细胞激活在 AD 进展中的能力。 大脑 CD8+ TRM 触发先天免疫细胞激活，包括 NK 细胞、小胶质细胞和巨噬细胞 AD 小鼠模型，ii) 确定大脑 CD8+ TRM 激活对阿尔茨海默病进展的影响 在小鼠中，包括认知和病理学，以及 iii) 确定迁移动态、丰度和克隆性 CD8+ TRM 在小鼠和人类 AD 大脑中的作用将通过补充经典来实现。 通过与现场持续合作研究小鼠模型 TRM 的免疫学技术 神经病理学家研究 AD 和非神经系统相关大脑死后组织中的 T 细胞 总的来说，这些实验将增强我们对 CD8+ 作用的理解。 TRM 在阿尔茨海默病中的应用，并有可能深入了解其他神经系统疾病中的 T 细胞功能， 揭示新的治疗靶点，并全面建立对大脑 TRM 功能的基础了解。