Nature Communications, Published online: 12 May 2026; doi:10.1038/s41467-026-73003-5 Prion diseases cause neurodegeneration associated with microglial alteration. Here, the authors show in a prion disease mouse model that phagocytic Gpnmb⁺ microglial state reflects regional responses to cell death and lysosomal stress rather than direct sensing of amyloid fibrils.