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<p>The COVID-19 pandemic has precipitated a surge in neurocognitive dysfunction, with long-term implications for global health systems and socioeconomic stability. Despite growing clinical recognition of post-COVID cognitive deficits (“brain fog”), the molecular mechanisms driving these impairments remain poorly understood. Our study addresses this critical gap by identifying SARS-CoV-2 nucleocapsid protein (SARS-CoV-2&#xa0;N protein), a core structural component of the virus, as a novel etiological factor in senescence-mediated cognitive decline. We observed that SARS-CoV-2&#xa0;N protein caused microglial senescence both in vivo and in vitro. Mechanistically, SARS-CoV-2&#xa0;N protein-induced metabolic shifting toward glycolysis initiated a cascade of microglial senescence, which propagated cognitive impairment. We found that glycolysis inhibition reduced SARS-CoV-2&#xa0;N protein-triggered microglial senescence and attenuated cognitive impairment in mice. Disrupted mitochondrial dynamics impaired oxidative phosphorylation capacity, forcing glycolytic reprogramming that ultimately triggered cellular senescence activation. We found that the SARS-CoV-2&#xa0;N protein promoted excessive mitochondrial dysfunction in microglia, resulting in mitochondrial fragmentation. Inhibition of mitochondrial fission effectively rescued SARS-CoV-2&#xa0;N protein-induced microglial senescence. In conclusion, our study suggests that the SARS-CoV-2&#xa0;N protein induces senescence-mediated cognitive impairment by promoting glycolysis in microglia. Therapeutic targeting of glycolysis in SARS-CoV-2&#xa0;N protein-triggered microglial senescence could be beneficial for treating or preventing cognitive impairment.</p>

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The SARS-CoV-2 nucleocapsid protein induces microglia senescence-mediated cognitive impairment via Glycolysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Nan-Shi-Yu Yang,
  • Han-Xi Sha,
  • Chen-Yu Zhang,
  • Hui Chen,
  • Yu-Biao Liu,
  • Jian-Bing Xiong,
  • Jia-Xi Duan,
  • Jun Zhang,
  • Cha-Xiang Guan,
  • Yong Zhou,
  • Feng Su,
  • Wen-Jing Zhong

摘要

The COVID-19 pandemic has precipitated a surge in neurocognitive dysfunction, with long-term implications for global health systems and socioeconomic stability. Despite growing clinical recognition of post-COVID cognitive deficits (“brain fog”), the molecular mechanisms driving these impairments remain poorly understood. Our study addresses this critical gap by identifying SARS-CoV-2 nucleocapsid protein (SARS-CoV-2 N protein), a core structural component of the virus, as a novel etiological factor in senescence-mediated cognitive decline. We observed that SARS-CoV-2 N protein caused microglial senescence both in vivo and in vitro. Mechanistically, SARS-CoV-2 N protein-induced metabolic shifting toward glycolysis initiated a cascade of microglial senescence, which propagated cognitive impairment. We found that glycolysis inhibition reduced SARS-CoV-2 N protein-triggered microglial senescence and attenuated cognitive impairment in mice. Disrupted mitochondrial dynamics impaired oxidative phosphorylation capacity, forcing glycolytic reprogramming that ultimately triggered cellular senescence activation. We found that the SARS-CoV-2 N protein promoted excessive mitochondrial dysfunction in microglia, resulting in mitochondrial fragmentation. Inhibition of mitochondrial fission effectively rescued SARS-CoV-2 N protein-induced microglial senescence. In conclusion, our study suggests that the SARS-CoV-2 N protein induces senescence-mediated cognitive impairment by promoting glycolysis in microglia. Therapeutic targeting of glycolysis in SARS-CoV-2 N protein-triggered microglial senescence could be beneficial for treating or preventing cognitive impairment.