TY  - JOUR
AU  - Schneeberger, Shirin
AU  - Kim, Seung Joon
AU  - Geesdorf, Maria N
AU  - Friebel, Ekaterina
AU  - Eede, Pascale
AU  - Jendrach, Marina
AU  - Boltengagen, Anastasiya
AU  - Braeuning, Caroline
AU  - Ruhwedel, Torben
AU  - Hülsmeier, Andreas J
AU  - Gimber, Niclas
AU  - Foerster, Marlene
AU  - Obst, Juliane
AU  - Andreadou, Myrto
AU  - Mundt, Sarah
AU  - Schmoranzer, Jan
AU  - Prokop, Stefan
AU  - Kessler, Wiebke
AU  - Kuhlmann, Tanja
AU  - Möbius, Wiebke
AU  - Nave, Klaus-Armin
AU  - Hornemann, Thorsten
AU  - Becher, Burkhard
AU  - Edgar, Julia M
AU  - Karaiskos, Nikos
AU  - Kocks, Christine
AU  - Rajewsky, Nikolaus
AU  - Heppner, Frank L
TI  - Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis.
JO  - Nature aging
VL  - 5
IS  - 4
SN  - 2662-8465
CY  - London
PB  - Nature Research
M1  - DZNE-2025-00536
SP  - 622 - 641
PY  - 2025
AB  - 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.
KW  - Alzheimer Disease: pathology
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: immunology
KW  - Alzheimer Disease: genetics
KW  - Animals
KW  - Humans
KW  - Signal Transduction
KW  - Mice
KW  - Oligodendroglia: metabolism
KW  - Oligodendroglia: pathology
KW  - Homeostasis
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Interleukin-12: metabolism
KW  - Interleukin-12: genetics
KW  - Mice, Transgenic
KW  - Male
KW  - Receptors, Interleukin-12: metabolism
KW  - Receptors, Interleukin-12: genetics
KW  - Brain: pathology
KW  - Brain: metabolism
KW  - Disease Models, Animal
KW  - Female
KW  - Microglia: metabolism
KW  - Aged
KW  - Amyloid beta-Peptides: metabolism
KW  - Receptors, Interleukin: metabolism
KW  - Receptors, Interleukin: genetics
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Interleukin-12 (NLM Chemicals)
KW  - Receptors, Interleukin-12 (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Receptors, Interleukin (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40082619
DO  - DOI:10.1038/s43587-025-00816-2
UR  - https://pub.dzne.de/record/278026
ER  -