Type I interferon drives T cell responses to amyloid beta in the central nervous system

Abstract Amyloid beta (Aβ) plaque deposition in the central nervous system (CNS) is a hallmark of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), triggering robust innate immune responses. However, the role of the adaptive immune system remains less well understood. Here we show the immune microenvironment dynamics in APP23 transgenic (APP23-tg) mice modelling CNS amyloid pathology, using single-cell transcriptomics. We observed a marked increase in T-cell populations during late disease stages, particularly CD8⁺ T-cells that clustered around Aβ plaques, suggesting a targeted immune response. Among these, we identified an Aβ plaque-associated subset of CD8⁺ T cells expressing interferon-stimulated genes (ISGs), which promoted Type-I interferon signaling. This subset also produced CXCL10, facilitating the recruitment of non-ISG T cells through the CXCL10-CXCR3 axis. Importantly, similar Type-I interferon responses were detected near plaques in human CNS amyloid pathology. Together, these findings highlight a shift from microglia-driven to T-cell-mediated neuroinflammation as amyloid pathology progresses, with implications for time-resolved therapy development.