Single-Cell RNA-Seq of PS2APP mouse hippocampi

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 characterize responses of twelve cell types in three different mouse models of Alzheimer's Disease, capturing the effects of tau-only, amyloid-only, or combined tau- amyloid pathology. We characterize microglia, oligodendrocyte, astrocyte, and T cell responses and compare them across these models. Notably, we identify two distinct transcriptional states for oligodendrocytes induced during disease and 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 accessible in the degenerating brain and how they are influenced by a key Alzheimer's Disease risk gene, Trem2. Overall design: RNA isolated from sorted hippocampi from female non-transgenic (n=3) and TauPS2APP (n=3) perfused at 7 months and male non-transgenic (n=3) and TauPS2APP mice (n=3) perfused at 15 months.