Abstract 4146396: Age-Associated CD8+ T Cells Accumulate in the Aging Brain

Introduction/Background: By 2050, the U.S. will see a demographic shift where individuals over 65 outnumber those under 65. This change underscores a rising prevalence of neurodegenerative diseases, particularly Alzheimer’s disease and various vascular dementias. Over the past 20 years, dementia cases have increased by 20% and are expected to triple in the next 30 years due to aging. The cerebral vasculature becomes increasingly stiff and blood-brain barrier molecules degenerate during aging, leading to accumulation of T cells in the aged brain. The role of T cells on neuroinflammation and dementia during aging is a key unanswered question. Research questions/Hypothesis: How does vascular impairment impact immune cells and inflammation in the brain? How does aging impact immune cells and inflammation in the brain? Goals/Aims: To quantify and characterize T cells within the brain during aging and in a model of vascular contributions to cognitive impairment and dementia (VCID). To determine interactions between brain-resident immune cells (glia) and T cells in aging and a model of VCID. Methods/Approach: We isolated T cells and microglia from 3-month old and 21-month old brains in a model of vascular contributions to cognitive impairment and dementia (VCID). We performed single-cell RNA sequencing to identify and characterize peripheral and resident immune cells in the brain in the setting of typical aging and a model of VCID. Results: We identified a substantial increase in Gzmk + expressing effector memory CD8+ T cells in the brains of 21-month-old mice compared to 3-month-old mice. These cells were distinguished by their unique transcriptome, cytokine secretion profiles, and accumulation patterns. We also found a significant shift of microglia from an anti-inflammatory expression pattern toward a pro-inflammatory profile in the VCID group compared to control. Conclusions: We found a significant accumulation of age-associated T cells which may promote dementias. This study highlights the importance of using aged animal models to understand the cellular dynamics of chronic inflammatory diseases and dementias, potentially guiding the development of targeted therapeutic strategies.