Journal Article

DZNE-2025-00536

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis.

Schneeberger, S. ; Kim, S. J. ; Geesdorf, M. N. ; Friebel, E.Extern* ; 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. ; Heppner, F. L. (Last author)DZNE*

2025
Nature Research London

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Please use a persistent id in citations: doi:10.1038/s43587-025-00816-2

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.

Keyword(s): Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: immunology (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Signal Transduction (MeSH) ; Mice (MeSH) ; Oligodendroglia: metabolism (MeSH) ; Oligodendroglia: pathology (MeSH) ; Homeostasis (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Interleukin-12: metabolism (MeSH) ; Interleukin-12: genetics (MeSH) ; Mice, Transgenic (MeSH) ; Male (MeSH) ; Receptors, Interleukin-12: metabolism (MeSH) ; Receptors, Interleukin-12: genetics (MeSH) ; Brain: pathology (MeSH) ; Brain: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Female (MeSH) ; Microglia: metabolism (MeSH) ; Aged (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Receptors, Interleukin: metabolism (MeSH) ; Receptors, Interleukin: genetics (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Interleukin-12 ; Receptors, Interleukin-12 ; Amyloid beta-Peptides ; Receptors, Interleukin ; Amyloid beta-Protein Precursor

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Contributing Institute(s):

1. Neuroimmunology (AG Heppner)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Nature ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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