Although prion infections cause cognitive impairment and neuronal death, transcriptional and translational profiling shows progressive derangement within glia but surprisingly little changes within neurons. Here we expressed PrP C selectively in neurons, astrocytes or oligodendrocytes of mice. After prion infection, both astrocyte and neuron-restricted PrP C expression led to copious brain accumulation of PrP Sc . As expected, neuron-restricted expression was associated with typical prion disease. However, mice with astrocyte-restricted PrP C expression experienced a normal life span, did not develop clinical disease, and did not show astro- or microgliosis. Besides confirming that PrP Sc is innocuous to PrP C -deficient neurons, these results show that astrocyte-born PrP Sc does not activate the extreme neuroinflammation that accompanies the onset of prion disease and precedes any molecular changes of neurons. This points to a nonautonomous mechanism by which prion-infected neurons instruct astrocytes and microglia to acquire a specific cellular state that, in turn, drives neural dysfunction.