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

COVID-19-associated cognitive dysfunction has emerged as a significant public health challenge, creating substantial socioeconomic burdens for affected individuals, their families, and healthcare systems. Our study found that the SARS-CoV-2 nucleocapsid protein (SARS-CoV-2 N protein), the fundamental architectural element of viral particles, as a novel molecular driver of neurocognitive impairment. We observed that N protein caused microglial senescence both in vivo and in vitro . Mechanistically, N protein-induced metabolic shifting toward glycolysis initiates a cascade of microglial senescence that propagates cognitive impairment. We found that glycolysis inhibition inhibited N protein-triggered microglial senescence and attenuated cognitive impairment in mice. Disrupted mitochondrial dynamics impair oxidative phosphorylation capacity, forcing glycolytic reprogramming that ultimately triggers cellular senescence activation. We found that the N protein promotes excessive mitochondrial dysfunction in microglia, resulting in mitochondrial fragmentation. Inhibition of mitochondrial fission effectively rescued N protein-induced microglial senescence in microglia. In conclusion, our study suggests that the N protein induces senescence-mediated cognitive impairment by promoting glycolysis in microglia. Therapeutic targeting of glycolysis in N protein-triggered microglial senescence could be beneficial for treating or preventing cognitive impairment.