TREM2-independent oligodendrocyte, astrocyte, and T cell responses to tau and amyloid pathology in mouse models of Alzheimer disease

Non-neuronal responses in neurodegenerative disease have received increasing attention as important contributors to disease pathogenesis and progression. Here we utilize single-cell RNA sequencing to broadly profile 13 cell types in three different mouse models of Alzheimer disease (AD), capturing the effects of tau-only, amyloid-only, or combined tau-amyloid pathology. We highlight microglia, oligodendrocyte, astrocyte, and T cell responses and compare them across these models. Notably, we identify two distinct transcriptional states for oligodendrocytes emerging differentially across disease models, and we determine their spatial distribution. Furthermore, we explore the impact of Trem2 deletion in the context of combined pathology. Trem2 knockout mice exhibit severely blunted microglial responses to combined tau and amyloid pathology, but responses from non-microglial cell types (oligodendrocytes, astrocytes, and T cells) are relatively unchanged. These results delineate core transcriptional states that are engaged in response to AD pathology, and how they are influenced by a key AD risk gene, Trem2. [Display omitted] •Census of 13 cell types across three separate AD models using scRNA-seq•Identification of two distinct oligodendrocyte states from different disease contexts•Elevation of T cell numbers in three AD models•Oligodendrocyte, astrocyte, and T cell responses occur with or without Trem2 deletion Lee et al. characterized glial and immune cell changes in different mouse models of Alzheimer disease using single-cell sequencing and histology. Microglial responses to pathology are disrupted by Trem2 knockout, but responses from other key cell types are relatively unperturbed.