UC Irvine

Alzheimer’s Disease is the most common form of dementia and is the fifth-leading cause of death in people age 65 and older. Unfortunately, no cure currently exists, and the few treatment options may temporarily relieve symptoms but have limited long-term effectiveness. Recent genome-wide association studies (GWAS) have unearthed a strong link between immune-related genes and AD risk. Both the innate and adaptive immune system have been implicated in the progression of AD, and much of the neuroinflammation that exists in this disease is thought to be related to an age-related decline in immune function. Microglia, the innate immune cells of the brain, become a large source of dysfunctional inflammation as they become chronically activated by the amyloid-beta (Aβ) plaques and tau tangles that aggregate in the AD brain. The protective functions of microglia are known to decline with age, yet it is still unclear what separates healthy and pathogenic aging of these cells. T cells, which typically exist in small numbers in the healthy brain, infiltrate the parenchyma in large numbers in response to AD-related inflammation. The mechanisms that recruit T cells to the brain and the effects that these cells have on pathology remain understudied, especially for CD8+ and γδ T cell subpopulations.

Chapter 1 of this dissertation explores the interaction of infiltrating T cells with amyloid plaques and tau tangles in AD model mice. In this study, we examined T cells from bone marrow transplantation studies and from immune-intact AD model mice using flow cytometry, immunohistochemistry, and single-cell RNA sequencing. We found evidence of significant infiltration of multiple T cell phenotypes in AD model mice, with CD8+ effector memory T cells forming the largest population. We also found clonal expansion of T cells from mice that developed Aβ pathology or Aβ and tau pathology, but not in mice with tau pathology alone, suggesting that early recruitment and clonal expansion of T cells is primarily amyloid-driven. These experiments provide an important resource for future investigations into the role of CD8+ T cells in AD.

Chapter 2 of this dissertation describes the creation of a model of premature aging in human iPSC- derived microglia, which was developed to facilitate research into human-specific age-related dysfunction in microglia. To create an aged phenotype in iPSCs, we induced homozygous genetic knockout of ERCC1, a critical DNA repair enzyme that causes progeroid diseases in patients with near-total loss of ERCC1 expression. In vitro assays and single-cell RNA sequencing of xenotransplanted microglia reveal signs of immune dysfunction, early senescence, and an increase in pro-inflammatory interferon signaling in ERCC1 KO microglia that may indicate a more aged phenotype. While further examination of this model is required, ERCC1 KO in iPSCs provides a platform for testing age-related microglial dysfunction in AD and other neuroinflammatory diseases.