Astrocytic Stat3 is dispensable for prion disease progression despite its role in neuroinflammation

Abstract Prion diseases are fatal proteinopathies caused by the misfolding of the host-derived prion protein, leading to neurodegeneration and neuroinflammation in the brain. Although prion disease has been extensively studied, the cellular pathways contributing to gliosis and neuronal loss remain incompletely understood. One of the initial hallmarks as prion disease progresses is astrocyte activation, along with the upregulation and phosphorylation of Signal Transducer and Activator of Transcription 3 ( Stat3 ). We generated conditional knockout mice to selectively delete Stat3 in activated astrocytes and infected them with RML prions. Brain tissue was collected at multiple timepoints and compared with prion-infected and uninfected littermates using immunoblotting, qRT-PCR, immunohistology, and immunofluorescence microscopy. Immunofluorescence microscopy demonstrated that astrocyte-specific upregulation and nuclear translocation of Stat3 was eliminated in prion-infected conditional knockout mice compared to prion-infected wildtype littermates. Deletion of Stat3 in activated astrocytes reduced both total and phosphorylated Stat3 levels in the prion-infected brain. This coincided with a loss of upregulation of several inflammatory and astrogliosis-related transcripts but not all. In contrast, microgliosis, prion deposition, vacuolation, and overall disease progression were unchanged by astrocytic Stat3 deletion. Although the Jak-Stat3 pathway is required for full astrocyte activation during prion infection, loss of Stat3 expression in activated astrocytes does not significantly alter disease outcome. These findings suggest that targeting Jak-Stat3 signaling is unlikely to provide therapeutic benefit in prion disease.