Temporal Dynamics of APOE and TREM2 Expression in Microglial Activation of NMOSD Mouse Models.

Journal: Molecular neurobiology
Published Date: Jun 23, 2025

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune demyelinating disease characterized by recurrent neuroinflammation and disability. Microglial activation plays a critical role in NMOSD pathogenesis, yet the mechanisms regulating its temporal dynamics remain poorly understood. The interplay between apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2), key regulators of microglial function in neurodegenerative diseases, has not yet been explored in NMOSD. We conducted bulk RNA-seq in NMOSD mouse models and integrated transcriptomic sequencing, bioinformatics, and machine learning (LASSO, SVM-RFE, random forest) to identify microglia-associated hub genes in an NMOSD mouse model. Immune cell infiltration was analyzed via ImmuCC. Candidate genes were validated using Western blotting and immunofluorescence. Temporal microglial activation and APOE/TREM2 expression were assessed at 3, 7, and 10 days postmodeling. Transcriptomic analysis identified 94 microglia-associated differentially expressed genes (MDEGs), with APOE and TREM2 emerging as central hubs through machine learning. ImmuCC revealed significant infiltration of macrophages, likely indicating microglial polarization. APOE and TREM2 expression peaked on day 3 postinduction, which was correlated with maximal microglial activation (IBA1 +), followed by a gradual decrease. Experimental validation confirmed elevated APOE and TREM2 protein levels in NMOSD mice, with immunofluorescence showing colocalization in activated microglia. This study establishes the APOE-TREM2 axis as a critical regulator of microglial activation in NMOSD, exhibiting early proinflammatory and later reparative roles. The biphasic expression pattern aligns with microglial phenotypic switching, suggesting therapeutic potential for stage-specific interventions. Our findings bridge computational predictions with experimental validation, offering novel insights into NMOSD mechanisms and actionable targets for therapy.

Authors

  • Si Xu
    Department of Neurology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  • Wentao Dai
    Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasm, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai-MOST Key Laboratory of Health and Disease Genomics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China; Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai, 201203, China. Electronic address: wtdai@scbit.org.
  • Tianfeng Wang
    Department of Intensive Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China.
  • Shugang Cao
    Department of Neurology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  • Jing Du
    Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute Shanghai 200233, China.
  • Xiaonan Pang
    Department of Neurology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  • Qi Li
    The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China.
  • Yanghua Tian
    4Department of Neurology, The First Hospital of Anhui Medical University, Hefei 230022, P. R. China.

Keywords

No keywords available for this article.

External Resources

Popular Topics
Recent Journals