Type-I Interferon drives T-cell responses to Amyloid-beta in the central nervous system

Amyloid beta (Aß) plaque deposition in the central nervous system (CNS) is a hallmark of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), triggering an innate immune response. However, the role of the adaptive immune system is less clear. We investigated immune microenvironment dynamics in APP23 transgenic (APP23-tg) mice modelling CNS amyloid pathology, using single-cell transcriptomics. A significant increase in T-cell populations, particularly CD8+ T-cells, was observed in late stages, clustering around Aß plaques, indicating a targeted response. A novel Aß plaque-associated subset of CD8+ T-cells expressing interferon-stimulated genes (ISGs), was found to drive Type-I interferon responses. This subset also produced CXCL10, which mediated non-ISG T-cell trafficking via the CXCL10-CXCR3 axis. Importantly, we corroborated our observations by identifying similar Type-I interferon responses near plaques in human CNS amyloid pathology. These findings highlight a shift from microglia-driven to T-cell-mediated neuroinflammation as amyloid pathology progresses, with implications for time-resolved therapy development. Overall design: to investigate the immune landscape in response to amyloid beta deposition we analysed RNAseq data of mouse brain immune cells (CD45+); comparison between APP23 transgenic mice vs wildtype littermates; two difffernt time points used: 14-month old mice and 24-month old mice;