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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

基本信息

批准号：
10693931
负责人：
Pamela Rosato
金额：
$ 65.22万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
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/10693931
关键词：
3xTg-AD mouse Acceleration Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Amyloid Antigens Area Atlases Automobile Driving Autopsy Brain CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Cellular biology Cerebrospinal Fluid Clonal Expansion Clonality Cognition Collaborations Complement Data Deposition Development Disease Disease Outcome Disease Progression Flow Cytometry Goals Histologic Human Immune Immunologic Surveillance Immunologic Techniques Immunotherapy Impaired cognition Individual Knock-out Knowledge Longitudinal Studies Macrophage 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 Reaction Reporting Research Role Site Synapses T cell clonality T cell receptor repertoire sequencing T-Cell Activation T-Cell Depletion T-Lymphocyte Testing Tissue Model Tissues behavior test brain shape brain tissue cell motility experimental study extracellular familial Alzheimer disease immune activation improved innovation insight migration mouse model nervous system disorder neuroinflammation neuropathology new therapeutic target novel protein aggregation recruit response single-cell RNA sequencing tau Proteins tissue resident memory T cell translational study

项目摘要

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.

项目总结/文摘