Glial activation in prion diseases is selectively triggered by neuronal PrP^Sc

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 and astrocytes 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.