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Here we expressed PrP<jats:sup>C<\/jats:sup> selectively in neurons and astrocytes of mice. After prion infection, both astrocyte and neuron\u2010restricted PrP<jats:sup>C<\/jats:sup> expression led to copious brain accumulation of PrP<jats:sup>Sc<\/jats:sup>. As expected, neuron\u2010restricted expression was associated with typical prion disease. However, mice with astrocyte\u2010restricted PrP<jats:sup>C<\/jats:sup> expression experienced a normal life span, did not develop clinical disease, and did not show astro\u2010 or microgliosis. Besides confirming that PrP<jats:sup>Sc<\/jats:sup> is innocuous to PrP<jats:sup>C<\/jats:sup>\u2010deficient neurons, these results show that astrocyte\u2010born PrP<jats:sup>Sc<\/jats:sup> 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\u2010infected neurons instruct astrocytes and microglia to acquire a specific cellular state that, in turn, drives neural dysfunction.<\/jats:p>","DOI":"10.1111\/bpa.13056","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T02:19:51Z","timestamp":1645150791000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Glial activation in prion diseases is selectively triggered by neuronal PrP<sup>Sc<\/sup>"],"prefix":"10.1111","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8752-148X","authenticated-orcid":false,"given":"Asvin K. 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