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005     20250504001206.0
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037 _ _ |a DZNE-2025-00536
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Schneeberger, Shirin
|b 0
245 _ _ |a Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis.
260 _ _ |a London
|c 2025
|b Nature Research
336 7 _ |a article
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520 _ _ |a 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.
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650 _ 7 |a Interleukin-12
|0 187348-17-0
|2 NLM Chemicals
650 _ 7 |a Receptors, Interleukin-12
|2 NLM Chemicals
650 _ 7 |a Amyloid beta-Peptides
|2 NLM Chemicals
650 _ 7 |a Receptors, Interleukin
|2 NLM Chemicals
650 _ 7 |a Amyloid beta-Protein Precursor
|2 NLM Chemicals
650 _ 2 |a Alzheimer Disease: pathology
|2 MeSH
650 _ 2 |a Alzheimer Disease: metabolism
|2 MeSH
650 _ 2 |a Alzheimer Disease: immunology
|2 MeSH
650 _ 2 |a Alzheimer Disease: genetics
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Signal Transduction
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Oligodendroglia: metabolism
|2 MeSH
650 _ 2 |a Oligodendroglia: pathology
|2 MeSH
650 _ 2 |a Homeostasis
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Neurons: pathology
|2 MeSH
650 _ 2 |a Interleukin-12: metabolism
|2 MeSH
650 _ 2 |a Interleukin-12: genetics
|2 MeSH
650 _ 2 |a Mice, Transgenic
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Receptors, Interleukin-12: metabolism
|2 MeSH
650 _ 2 |a Receptors, Interleukin-12: genetics
|2 MeSH
650 _ 2 |a Brain: pathology
|2 MeSH
650 _ 2 |a Brain: metabolism
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Microglia: metabolism
|2 MeSH
650 _ 2 |a Aged
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: metabolism
|2 MeSH
650 _ 2 |a Receptors, Interleukin: metabolism
|2 MeSH
650 _ 2 |a Receptors, Interleukin: genetics
|2 MeSH
650 _ 2 |a Amyloid beta-Protein Precursor: genetics
|2 MeSH
700 1 _ |a Kim, Seung Joon
|b 1
700 1 _ |a Geesdorf, Maria N
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700 1 _ |a Friebel, Ekaterina
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700 1 _ |a Eede, Pascale
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700 1 _ |a Jendrach, Marina
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700 1 _ |a Boltengagen, Anastasiya
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700 1 _ |a Braeuning, Caroline
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700 1 _ |a Ruhwedel, Torben
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700 1 _ |a Hülsmeier, Andreas J
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700 1 _ |a Gimber, Niclas
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700 1 _ |a Foerster, Marlene
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700 1 _ |a Obst, Juliane
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700 1 _ |a Andreadou, Myrto
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700 1 _ |a Mundt, Sarah
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700 1 _ |a Schmoranzer, Jan
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700 1 _ |a Prokop, Stefan
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700 1 _ |a Kessler, Wiebke
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700 1 _ |a Kuhlmann, Tanja
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700 1 _ |a Möbius, Wiebke
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700 1 _ |a Nave, Klaus-Armin
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700 1 _ |a Hornemann, Thorsten
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700 1 _ |a Becher, Burkhard
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700 1 _ |a Edgar, Julia M
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700 1 _ |a Karaiskos, Nikos
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700 1 _ |a Kocks, Christine
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700 1 _ |a Rajewsky, Nikolaus
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700 1 _ |a Heppner, Frank L
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773 _ _ |a 10.1038/s43587-025-00816-2
|g Vol. 5, no. 4, p. 622 - 641
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