Role of CD8 T cell in the pathogenesis of Alzheimer's disease

National Institute On Aging

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Abstract

Neuroinflammation is a hallmark of Alzheimers disease (AD) resulting from dysregulation of the innate immune cells. Recent studies show clonally expanded CD8+ T cells are present in the brain and CSF of AD patients, suggesting the adaptive immune cells may be involved in AD pathogenesis. Activated by antigen, CD8+ T cells kill infected or cancerous cells and produce proinflammatory cytokines and chemokines, modulating the immune response. We hypothesize that CD8+ T cells that infiltrate the brain contribute to the pathological course of AD via production of proinflammatory cytokines and cytotoxicity in an antigen-specific manner. We propose to test that hypothesis using three specific aims. First, using three mouse models of AD (APP/PS1, 5xFAD, and 3xTg) we will identify and characterize CD8+ T cells in the brain and CSF. We will analyze their phenotype, differentiation state and T cell receptor (TCR) sequence. Second, we will determine if CD8+ T cells in the brain affect the pathological course of AD in these models by generating AD mice that lack CD8+ T cells. We will then delineate the roles of proinflammatory cytokines IFN and TNFversus the cytotoxic effects of Perforin and Fasl in this pathology. Finally, we will examine the TCRs found to be most expanded and their potential antigens, and determine their contributions in the pathogenesis of AD. Together, these studies will reveal the role of CD8+ T cells in the pathogenesis of AD mouse models.