%0 Journal Article
%A Schneeberger, Shirin
%A Kim, Seung Joon
%A Geesdorf, Maria N
%A Friebel, Ekaterina
%A Eede, Pascale
%A Jendrach, Marina
%A Boltengagen, Anastasiya
%A Braeuning, Caroline
%A Ruhwedel, Torben
%A Hülsmeier, Andreas J
%A Gimber, Niclas
%A Foerster, Marlene
%A Obst, Juliane
%A Andreadou, Myrto
%A Mundt, Sarah
%A Schmoranzer, Jan
%A Prokop, Stefan
%A Kessler, Wiebke
%A Kuhlmann, Tanja
%A Möbius, Wiebke
%A Nave, Klaus-Armin
%A Hornemann, Thorsten
%A Becher, Burkhard
%A Edgar, Julia M
%A Karaiskos, Nikos
%A Kocks, Christine
%A Rajewsky, Nikolaus
%A Heppner, Frank L
%T Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis.
%J Nature aging
%V 5
%N 4
%@ 2662-8465
%C London
%I Nature Research
%M DKFZ-2025-00565
%P 622-641
%D 2025
%Z 2025 Apr;5(4):622-641
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40082619
%R 10.1038/s43587-025-00816-2
%U https://inrepo02.dkfz.de/record/299828