Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19

SARS-CoV-2 infection is associated with long-lasting neurological symptoms, although the underlying mechanisms remain unclear. Using optical clearing and imaging, we observed the accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis of human COVID-19 patients, persisting long after viral clearance. Further, biomarkers of neurodegeneration were elevated in the cerebrospinal fluid from long COVID patients, and proteomic analysis of human skull, meninges, and brain samples revealed dysregulated inflammatory pathways and neurodegeneration-associated changes. Similar distribution patterns of the spike protein were observed in SARS-CoV-2-infected mice. Injection of spike protein alone was sufficient to induce neuroinflammation, proteome changes in the skull-meninges-brain axis, anxiety-like behavior, and exacerbated outcomes in mouse models of stroke and traumatic brain injury. Vaccination reduced but did not eliminate spike protein accumulation after infection in mice. Our findings suggest persistent spike protein at the brain borders may contribute to lasting neurological sequelae of COVID-19. [Display omitted] •SARS-CoV-2 spike protein persists in the skull-meninges-brain axis in COVID-19 patients•Spike protein is sufficient to induce brain pathological and behavioral changes in mice•Spike protein enhances brain vulnerability and exacerbates neurological damage in mice•mRNA vaccines reduce, but do not eliminate, the spike burden SARS-CoV-2 infection can lead to long-lasting neurological sequelae, but underlying mechanisms are unclear. Rong et al. report that SARS-CoV-2 spike protein persists in the skull-meninges-brain axis, inducing inflammation, neurodegeneration-related changes, and increasing the brain’s vulnerability to further injury.