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.