Downregulation of STAT3 transcription factor reverses synaptotoxic phenotype of reactive astrocytes associated with prion diseases

In neurodegenerative diseases, including prion diseases, astrocytes adopt reactive phenotypes that persist throughout disease progression. While astrocyte reactivity may initially serve as a protective response to prion infection, it transitions into a neurotoxic phenotype that disrupts homeostatic functions and exacerbates disease pathology. The transcription factor Stat3 has been recognized as a master regulator of astrocyte reactivity in neurodegenerative diseases, yet its role in prion disease-associated astrocyte reactive phenotypes remains unexplored. The current study addresses this gap by investigating the effects of Stat3 deletion in reactive astrocytes isolated from prion-infected mice. We demonstrate that Stat3 deletion mitigates the reactive astrocyte phenotype and alleviates their synaptotoxic effects. Stat3-dependent activation of astrocytes was reproduced by co-culturing naïve astrocytes with reactive microglia isolated from prion-infected animals or exposing them to microglia-conditioned media. A cytokine array profiling of 40 molecules revealed partially overlapping inflammatory signatures in reactive microglia and astrocytes, with IL-6 prominently upregulated in both cell types. Notably, IL-6 treatment elevated phosphorylated Stat3 levels in naïve astrocytes and triggered astrocyte reactivity. These findings indicate that the synaptotoxic phenotype of astrocytes in prion diseases can be sustained by reactive microglia and self-reinforced in a cell-autonomous manner. Our work highlights the pivotal role of Stat3 signaling in astrocyte activation and suggests that Stat3 inhibition may suppress the reactive phenotype of astrocytes associated with prion diseases.