(1) C3+-astrocytes (A1-like-astrocytes) were abundant in mouse and human prion diseases. (2) Mice lacking TNF-α, IL-1α and C1qa had accelerated prion disease course (measured by survival rate) without affecting the formation of PrPSc and microglial activation. (3) C3 expression was significantly up-regulated and C3+-astrocytes significantly increased in the thalamus of terminally sick WT but not in Triple deficient mice. Here, TNF is linked to prion disease.