SARS-CoV-2 spike protein induces long-term TLR4-mediated synapse and cognitive loss recapitulating Post-COVID syndrome

Fontes-Dantas, F. L.; Fernandes, G. G.; Gutman, E. G.; De Lima, E. V.; Antonio, L. S.; Hammerle, M. B.; Mota-Araujo, H. P.; Colodeti, L. C.; Araujo, S. M. B.; da Silva, T. N.; Duarte, L. A.; Salvio, A. L.; Pires, K. L.; Leon, L. A. A.; Vasconcelos, C. C. F.; Romao, L.; Savio, L. E. B.; Silva, J. L.; da Costa, R.; Clarke, J. R.; Da Poian, A. T.; Alves-Leon, S. V.; Passos, G. F.; Figueiredo, C. P.

doi:10.1101/2022.06.07.495149

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bioRxiv · 10.1101/2022.06.07.495149

SARS-CoV-2 spike protein induces long-term TLR4-mediated synapse and cognitive loss recapitulating Post-COVID syndrome

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Abstract

Cognitive dysfunction is often reported in post-COVID patients, but its underlying mechanisms remain unknown. While some evidence indicate that SARS-CoV-2 can reach and directly impact the brain, others suggest viral neuroinvasion as a rare event. Independently of brain viral infection, the ability of SARS-CoV-2 spike (S) protein to cross the BBB and reach memory-related brain regions has already been shown. Here, we demonstrate that brain infusion of S protein in mice induces late cognitive impairment and increases serum levels of neurofilament light chain (NFL), which recapitulates post-COVID features. Neuroinflammation, hippocampal microgliosis and synapse loss are induced by S protein. Increased engulfment of hippocampal presynaptic terminals late after S protein brain infusion were found to temporally correlate with cognitive deficit in mice. Blockage of TLR4 signaling prevented S-associated detrimental effects on synapse and memory loss. In a cohort of 86 patients recovered from mild COVID-19, genotype GG TLR4 -2604G>A (rs10759931) was associated with poor cognitive outcome. Collectively, these findings indicate that S protein directly impacts the brain and suggest that TLR4 is a potential target to prevent post-COVID cognitive dysfunction. One Sentence SummaryTLR4 mediates long-term cognitive impairment in mice and its genetic variant increases the risk of poor cognitive outcome in post-COVID patients.

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Fontes-Dantas, F. L., Fernandes, G. G., Gutman, E. G., De Lima, E. V., Antonio, L. S., Hammerle, M. B., Mota-Araujo, H. P., Colodeti, L. C., Araujo, S. M. B., da Silva, T. N., Duarte, L. A., Salvio, A. L., Pires, K. L., Leon, L. A. A., Vasconcelos, C. C. F., Romao, L., Savio, L. E. B., Silva, J. L., da Costa, R., Clarke, J. R., Da Poian, A. T., Alves-Leon, S. V., Passos, G. F., Figueiredo, C. P.. 2022-06-08. SARS-CoV-2 spike protein induces long-term TLR4-mediated synapse and cognitive loss recapitulating Post-COVID syndrome. https://doi.org/10.1101/2022.06.07.495149

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