NG2 glia protect against prion neurotoxicity by inhibiting prostaglandin E2 signaling

Oligodendrocyte-lineage cells of patients and animal models undergo prominent changes in various neurodegenerative disorders. This raises the question of how myelinating cells interact with neurodegenerative processes. Here, we investigated the role of oligodendrocyte precursor cells (NG2 glia) in prion infections. We found that NG2 glia were activated in prion-infected cerebellar organotypic cultured slices (COCS) and in brains of prion-inoculated mice. In both model systems, depletion of NG2 glia exacerbated prion-induced neurodegeneration and accelerated prion pathology, suggesting a protective effect for NG2 glia. Loss of NG2 glia unleashed a microglial reaction promoting the biosynthesis of prostaglandin E2 (PGE2), which augmented prion toxicity in HovS cells and COCS through binding to the EP1 and EP4 receptors. Pharmacological or genetic inhibition of PGE2 biosynthesis attenuated prion-induced neurodegeneration in COCS and mice, antagonized the enhanced neurodegeneration in NG2 glia-depleted COCS and brains after prion infection, and dampened the acceleration of prion disease in NG2 glia-depleted mice. These data unveil a non-cell-autonomous interaction involving NG2 glia and microglia in prion disease and suggest that PGE2 signaling may represent an actionable target against prion diseases