SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice.
Cell Rep
; 42(3): 112189, 2023 03 28.
Article
in English
| MEDLINE | ID: covidwho-2240749
ABSTRACT
Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Cognitive Dysfunction
/
COVID-19
Type of study:
Cohort study
/
Observational study
/
Prognostic study
Topics:
Long Covid
Limits:
Animals
/
Humans
Language:
English
Journal:
Cell Rep
Year:
2023
Document Type:
Article
Affiliation country:
J.celrep.2023.112189
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