Infectious history as a determinant of age-related neuroinflammation and Alzheimer’s disease 3093

Abstract Description Alzheimer’s Disease (AD) is a neurodegenerative condition influenced by genetic and environmental factors, including chronic inflammation linked to aging. While microglia’s role in neuroinflammation is well-studied, the impact of T cells remains less clear. T cells can infiltrate the brain and form tissue-resident memory T cells (TRM), potentially influencing neurodegeneration. Current animal models, often studied in sterile conditions, lack the immune diversity seen in humans. To address this, we exposed WT and APP/PS1 mice (AD model) to various pathogens across their lifespan. Infection increased mortality, particularly in males, and caused hippocampus-dependent memory deficits in infected APP/PS1 females. CD8 T cell levels increase in the brains of both WT and AD mice after infection, with APP/PS1 mice showing CD8 TRM accumulation in regions like the hippocampus and cortex, near amyloid plaques and blood vessels. Elevated chemokines (Cxcl9 and Cxcl10) in APP/PS1 mice suggest endothelial cells and astrocytes mediate T-cell infiltration in the AD brain. Single-cell RNA sequencing identified expanded CD8 TRM cells expressing *Gzmk, IFNg,* and *CCL4/CCL5*. Infection enhances antigen presentation, interferon signaling, and chemokine interactions between CD8 T cells and microglia, suggesting induction of T cell-microglia crosstalk and activation. These findings highlight the interplay of infection, immune infiltration, and AD pathology, offering potential therapeutic insights. Funding Sources NIH R21 AG082156-01 AHA-Allen Iniciative Topic Categories Neuroimmunology (NEUR)