UC Irvine

Alzheimer’s Disease (AD) is the most common cause of age-related dementia and currently the sixth leading cause of deathin the United States. AD neuropathology is primarily characterized by the accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles that are composed of insoluble proteinaceous aggregates of beta-amyloid (Aβ) and tau. Although these hallmark AD pathologies have been well established and described in numerous studies, many other important pathological changes occur in the brains of AD patients including synaptic and neuronal loss and neuroinflammation. Most recently, genome-wide association studies (GWAS) have provided substantial new evidence that immune dysfunction may contribute to the development and progression of AD. To date over 60 GWAS loci have been identified and almost two thirds of these genes are highly expressed in microglia, the resident innate immune cell of the brain. These genetic discoveries have in turn inspired many new studies of microglial biology and the role of these cells in AD. In contrast, the role of the adaptive immunity in AD remains understudied, despite evidence that many of AD risk genes are also highly expressed in T and B cells. To investigate the role of T cell infiltration in AD, my thesis research utilized both bone marrow transplanted immune-deficient and immune intact transgenic mouse models of AD coupled with flow cytometry and single cell RNA sequencing. Taken together my experiments demonstrate that multiple T cell subtypes infiltrate the AD brain and effector memory CD8 T cells are specifically enriched in response to Aβ pathology or a combination of Aβ and Tau pathologies. Single-cell sequencing analysis of T-cell receptor (TCR) repertoires further reveal clonality dependent on amyloid; and high expression of several AD risk genes. Ultimately, this study further demonstrates the crucial importance of investigating the role of T cells in AD and provides a guide for future experiments to continue to enhance our understanding of AD immunology.