SARS-CoV-2 S1 protein causes brain inflammation by reducing intracerebral acetylcholine production

Neurological complications that occur in SARS-CoV-2 infection, such as olfactory dysfunction, brain inflammation, malaise, and depressive symptoms, are thought to contribute to long COVID. However, in autopsies of patients who have died from COVID-19, there is normally no direct evidence that central nervous system damage is due to proliferation of SARS-CoV-2. For this reason, many aspects of the pathogenesis mechanisms of such symptoms remain unknown. Expressing SARS-CoV-2 S1 protein in the nasal cavity of mice was associated with increased apoptosis of the olfactory system and decreased intracerebral acetylcholine production. The decrease in acetylcholine production was associated with brain inflammation, malaise, depressive clinical signs, and decreased expression of the cytokine degrading factor ZFP36. Administering the cholinesterase inhibitor donepezil to the mice improved brain inflammation, malaise and depressive clinical signs. These findings could contribute to the elucidation of the pathogenesis mechanisms of neurological complications associated with COVID-19 and long COVID.

Automated summary

Neurological complications in SARS-CoV-2 infection, including olfactory dysfunction, brain inflammation, malaise, and depressive symptoms, may contribute to long COVID. However, the direct evidence of central nervous system damage caused by SARS-CoV-2 proliferation is usually absent in autopsies of COVID-19 patients. Therefore, the pathogenesis mechanisms of these symptoms remain largely unknown. By expressing SARS-CoV-2 S1 protein in mouse nasal cavities, increased apoptosis of the olfactory system and decreased acetylcholine production in the brain were observed. The decrease in acetylcholine production was associated with brain inflammation, malaise, depressive clinical signs, and reduced expression of the cytokine degrading factor ZFP36. Administering the cholinesterase inhibitor donepezil to the mice improved brain inflammation, malaise, and depressive clinical signs. These findings provide insight into the pathogenesis mechanisms of neurological complications associated with COVID-19 and long COVID.