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| Item Type: | Article |
|---|---|
| Title: | Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis |
| Creators Name: | Schneeberger, S., Kim, S.J., Geesdorf, M.N., Friebel, E., Eede, P., Jendrach, M., Boltengagen, A., Braeuning, C., Ruhwedel, T., Hülsmeier, A.J., Gimber, N., Foerster, M., Obst, J., Andreadou, M., Mundt, S., Schmoranzer, J., Prokop, S., Kessler, W., Kuhlmann, T., Möbius, W., Nave, K.A., Hornemann, T., Becher, B., Edgar, J.M., Karaiskos, N., Kocks, C., Rajewsky, N. and Heppner, F.L. |
| Abstract: | Neuroinflammation including interleukin (IL)-12/IL-23-signaling is central to Alzheimer’s disease (AD) pathology. Inhibition of p40, a subunit of IL-12/IL-23, attenuates pathology in AD-like mice; however, its signaling mechanism and expression pattern remained elusive. Here we show that IL-12 receptors are predominantly expressed in neurons and oligodendrocytes in AD-like APPPS1 mice and in patients with AD, whereas IL-23 receptor transcripts are barely detectable. Consistently, deletion of the IL-12 receptor in neuroectodermal cells ameliorated AD pathology in APPPS1 mice, whereas removal of IL-23 receptors had no effect. Genetic ablation of IL-12 signaling alone reverted the loss of mature oligodendrocytes, restored myelin homeostasis, rescued the amyloid-β-dependent reduction of parvalbumin-positive interneurons and restored phagocytosis-related changes in microglia of APPPS1 mice. Furthermore, IL-12 protein expression was increased in human AD brains compared to healthy age-matched controls, and human oligodendrocyte-like cells responded profoundly to IL-12 stimulation. We conclude that oligodendroglial and neuronal IL-12 signaling, but not IL-23 signaling, are key in orchestrating AD-related neuroimmune crosstalk and that IL-12 represents an attractive therapeutic target in AD. |
| Keywords: | Animals, Mice |
| Source: | Nature Aging |
| ISSN: | 2662-8465 |
| Publisher: | Springer Nature |
| Date: | 13 March 2025 |
| Official Publication: | https://doi.org/10.1038/s43587-025-00816-2 |
| PubMed: | View item in PubMed |
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