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bioRxiv · 10.1101/2025.08.17.670762

Human aged astrocytes induce neurotoxicity in response to inflammatory stimuli

Kobayashi, H.·Maeda, K.·Wakui, T.·Kazetani, K.·Nabetani, A.·Shin, E.·Kato, H.·Endoh-Yamagami, S.
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Abstract

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- and IFN-{gamma}. Furthermore, astrocytes with senescent features showed even higher levels of neurotoxicity in the presence of TNF- and IFN-{gamma}, suggesting a potential link between aging and neurodegenerative diseases. It was also demonstrated that LPS-activated neuron/astrocyte/microglia tri-culture produced TNF-, leading to neurotoxicity in the tri-culture when IFN-{gamma} was present. Through compound screening, we identified Janus kinase inhibitors capable of preventing neurotoxicity in astrocytes induced by TNF- and IFN-{gamma}, 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.

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Kobayashi, H., Maeda, K., Wakui, T., Kazetani, K., Nabetani, A., Shin, E., Kato, H., Endoh-Yamagami, S.. 2025-08-18. Human aged astrocytes induce neurotoxicity in response to inflammatory stimuli. https://doi.org/10.1101/2025.08.17.670762

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