2. Academic Validation
  3. Ogt-mediated O-GlcNAcylation inhibits astrocytes activation through modulating NF-κB signaling pathway

Ogt-mediated O-GlcNAcylation inhibits astrocytes activation through modulating NF-κB signaling pathway

  • J Neuroinflammation. 2023 Jun 22;20(1):146. doi: 10.1186/s12974-023-02824-8.
Xiaoxue Dong # 1 2,  Liqi Shu # 3,  Jinyu Zhang # 1 2,  Xu Yang 1 2,  Xuejun Cheng 1,  Xingsen Zhao 1 2,  Wenzheng Qu 1,  Qiang Zhu 4,  Yikai Shou 1,  Guoping Peng 5,  Binggui Sun 6 7,  Wen Yi 8,  Qiang Shu 9,  Xuekun Li 10 11 12 13
Affiliations

Affiliations

  • 1 The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang University, Hangzhou, 310052, China.
  • 2 The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, China.
  • 3 Department of Neurology, The Warren Alpert Medical School of Brown University, Providence, RI, 02908, USA.
  • 4 MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 5 The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 6 The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang University, Hangzhou, 310052, China. [email protected].
  • 7 NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang, China. [email protected].
  • 8 MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China. [email protected].
  • 9 The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang University, Hangzhou, 310052, China. [email protected].
  • 10 The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang University, Hangzhou, 310052, China. [email protected].
  • 11 The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, China. [email protected].
  • 12 Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310029, China. [email protected].
  • 13 Binjiang Institute of Zhejiang University, Hangzhou, 310053, China. [email protected].
  • # Contributed equally.
PMID: 37349834 DOI: 10.1186/s12974-023-02824-8
Abstract

Previous studies have shown that Ogt-mediated O-GlcNAcylation is essential for neuronal development and function. However, the function of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in astrocytes remains largely unknown. Here we show that Ogt deficiency induces inflammatory activation of astrocytes in vivo and in vitro, and impairs cognitive function of mice. The restoration of O-GlcNAcylation via GlcNAc supplementation inhibits the activation of astrocytes, inflammation and improves the impaired cognitive function of Ogt deficient mice. Mechanistically, Ogt interacts with NF-κB p65 and catalyzes the O-GlcNAcylation of NF-κB p65 in astrocytes. Ogt deficiency induces the activation of NF-κB signaling pathway by promoting Gsk3β binding. Moreover, Ogt depletion induces the activation of astrocytes derived from human induced pluripotent stem cells. The restoration of O-GlcNAcylation inhibits the activation of astrocytes, inflammation and reduces Aβ plaque of AD mice in vitro and in vivo. Collectively, our study reveals a critical function of Ogt-mediated O-GlcNAcylation in astrocytes through regulating NF-κB signaling pathway.

Figures
Products