Interleukin-12 signaling drives Alzheimer’s disease pathology through disrupting neuronal and oligodendrocyte homeostasis
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.
Authors
- Marina Jendrach (ORCID: https://orcid.org/0000-0002-8601-2277)
- Andreas J. Hülsmeier
- Myrto Andreadou (ORCID: https://orcid.org/0000-0001-6757-4664)
- Sarah Mundt (ORCID: https://orcid.org/0000-0003-2169-2109)
- Julia M. Edgar (ORCID: https://orcid.org/0000-0002-3869-0962)
- Pascale Eede (ORCID: https://orcid.org/0000-0002-0272-8607)
- Klaus‐Armin Nave (ORCID: https://orcid.org/0000-0001-8724-9666)
- Wiebke Kessler
- Thorsten Hornemann (ORCID: https://orcid.org/0000-0002-4218-1087)
- Torben Ruhwedel (ORCID: https://orcid.org/0000-0002-9535-9395)
- Juliane Obst (ORCID: https://orcid.org/0000-0001-9534-8488)
- Maria Geesdorf
- Tanja Kuhlmann (ORCID: https://orcid.org/0000-0002-0174-5042)
- Burkhard Becher (ORCID: https://orcid.org/0000-0002-1541-7867)
- Ekaterina Friebel (ORCID: https://orcid.org/0000-0003-1419-2376)
- Niclas Gimber (ORCID: https://orcid.org/0000-0001-9456-3063)
- Jan Schmoranzer (ORCID: https://orcid.org/0000-0002-4482-7080)
- Seung Joon Kim (ORCID: https://orcid.org/0000-0003-4836-8958)
- Anastasiya Boltengagen (ORCID: https://orcid.org/0000-0002-8356-9766)
- Nikolaus Rajewsky (ORCID: https://orcid.org/0000-0002-4785-4332)
- Christine Kocks (ORCID: https://orcid.org/0000-0003-1749-3334)
- Caroline Braeuning (ORCID: https://orcid.org/0009-0007-1439-9920)
- Frank L. Heppner (ORCID: https://orcid.org/0000-0001-9816-8917)
- Nikos Karaiskos (ORCID: https://orcid.org/0000-0001-7771-3947)
- Shirin Schneeberger
- Stefan Prokop (ORCID: https://orcid.org/0000-0002-5633-2149)
- Marlene Foerster
- Wiebke Möbius (ORCID: https://orcid.org/0000-0002-2902-7165)
Institutions
- German Cancer Research Center (DE)
- University of Zurich (CH)
- Max Delbrück Center (DE)
- German Center for Neurodegenerative Diseases (DE)
- University of Florida (US)
- Humboldt-Universität zu Berlin (DE)
- German Cancer Society (DE)
- University Hospital Münster (DE)
- German Centre for Higher Education Research and Science Studies (DE)
- National Center for Tumor Diseases (DE)
- German Centre for Cardiovascular Research (DE)
- Berliner Wasserbetriebe (Germany) (DE)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
- University of Glasgow (GB)
Publication Details
- Journal
- Nature Aging
- Published
- 2025-03-13
- DOI
- https://doi.org/10.1038/s43587-025-00816-2
- Citations
- 18
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 15.16