Human aged astrocytes induce neurotoxicity in response to inflammatory stimuli

Astrocytes play a critical role in neuroinflammation and the pathogenesis of neurodegenerative diseases. Here we found that human induced pluripotent stem cell (iPSC)-derived astrocytes responded differently to inflammatory triggers compared to rodent astrocytes, showing increased neurotoxicity when exposed to TNF-α and IFN-γ. Furthermore, astrocytes with senescent features showed even higher levels of neurotoxicity in the presence of TNF-α and IFN-γ, suggesting a potential link between aging and neurodegenerative diseases. It was also demonstrated that LPS-activated neuron/astrocyte/microglia tri-culture produced TNF-α, leading to neurotoxicity in the tri-culture when IFN-γ was present. Through compound screening, we identified Janus kinase inhibitors capable of preventing neurotoxicity in astrocytes induced by TNF-α and IFN-γ, demonstrating the potential use of neurotoxic astrocytes as a platform for drug screening. These results provide insight into the complex relationship between aging, inflammation, and neurodegenerative diseases, emphasizing the potential of targeting astrocytes as a novel therapeutic approach for addressing neurodegenerative diseases.