Scholarlink

<p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Interleukin-12 signaling drives Alzheimer’s disease pathology through disrupting neuronal and oligodendrocyte homeostasis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月13日

查看全文
  • Shirin Schneeberger,
  • Seung Joon Kim,
  • Maria N. Geesdorf,
  • Ekaterina Friebel,
  • Pascale Eede,
  • Marina Jendrach,
  • Anastasiya Boltengagen,
  • Caroline Braeuning,
  • Torben Ruhwedel,
  • Andreas J. Hülsmeier,
  • Niclas Gimber,
  • Marlene Foerster,
  • Juliane Obst,
  • Myrto Andreadou,
  • Sarah Mundt,
  • Jan Schmoranzer,
  • Stefan Prokop,
  • Wiebke Kessler,
  • Tanja Kuhlmann,
  • Wiebke Möbius,
  • Klaus-Armin Nave,
  • Thorsten Hornemann,
  • Burkhard Becher,
  • Julia M. Edgar,
  • Nikos Karaiskos,
  • Christine Kocks,
  • Nikolaus Rajewsky,
  • Frank L. Heppner

摘要

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.