Gpnmb⁺ Microglia Represent a Distinct Subtype Reacting to Neuronal Loss induced by Prion Disease

Of all neurodegenerative pathologies, prion diseases exhibit one of the most extensive neuroinflammatory phenotypes, yet the impact of neuroinflammation on the course of the disease is anything but clear . Prions trigger conspicuous proliferation of microglial cells, which may contribute to neuronal damage but are also involved in prion clearance . We approached these questions by establishing a spatial-transcriptomic atlas of the progression of prion disease, and identified GPNMB gene as the most enriched one in a subset of microglial cells with enhanced phagocytic activity present only in prion-infected mice. This cell type responded to ongoing apoptosis in distinct brain regions from 30 weeks post-prion inoculation and progressively increased up to the terminal stage of the disease. Prion infected animals (RML6) and related (NBH) controls were sacrificed at 3 different timepoints during disease progression: 27 weeks post intraperitoneal injection (wpi), 30 wpi and terminal stage. OCT embedded brains were cut to generate 10 um thin-cryosections. Spatial transcriptomics was then performed by using 10x Genomics protocol.