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.