Semaglutide Attenuates Neuroinflammation in Mice

Rausch, D. M.; Ludwig, M. Q.; Bentsen, M. A.; Hansen, S. N.; Secher, A.; Holst, D.; Moreno, J.; Das, V.; Egerod, K. L.; Bjerregaard, A.-M.; Niss, K.; Bau, S.; Pyke, C.; Dalgaard, K.; Merkestein, M.; Wichern, F.; Hansen, C. T.; Polex-Wolf, J.; Bjerre Knudsen, L.; Pers, T. H.

doi:10.64898/2026.01.10.698763

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bioRxiv · 10.64898/2026.01.10.698763

Semaglutide Attenuates Neuroinflammation in Mice

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Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown promise in preclinical models of neurodegeneration, with emerging evidence suggesting these effects may be driven by modulation of neuroinflammation. However, the cellular mechanisms underlying GLP-1 RA effects on neuroinflammation remain poorly understood. Here, using a mouse model of lipopolysaccharide-induced neuroinflammation, we investigated how semaglutide coordinates cellular responses to resolve neuroinflammation. We find that semaglutide prevents brain infiltration of neutrophils, excessive cytokine release, and suppresses neuroinflammation-associated transcriptional signatures specifically in microglia, endothelial cells, and a subset of pericytes. Mechanistically, we identify a subset of Glp1r-expressing neurons in the dorsal vagal complex that, upon semaglutide treatment, regulate genes involved in anti-inflammatory signaling. Semaglutide-modulated pathways overlap with inflammatory signatures found in human neurodegenerative diseases, including Alzheimers disease, suggesting broad relevance for conditions involving neuroinflammation. Together, these findings reveal how GLP-1R signaling orchestrates resolution of neuroinflammation through coordinated multi-cellular programs.

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Rausch, D. M., Ludwig, M. Q., Bentsen, M. A., Hansen, S. N., Secher, A., Holst, D., Moreno, J., Das, V., Egerod, K. L., Bjerregaard, A.-M., Niss, K., Bau, S., Pyke, C., Dalgaard, K., Merkestein, M., Wichern, F., Hansen, C. T., Polex-Wolf, J., Bjerre Knudsen, L., Pers, T. H.. 2026-01-12. Semaglutide Attenuates Neuroinflammation in Mice. https://doi.org/10.64898/2026.01.10.698763

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