SARS-CoV-2 SPIKE PROTEIN INDUCES LONG-TERM COGNITIVE DYSFUNCTION RECAPITULATING POST-COVID-19 SYNDROME IN MICE

Cognitive impairment is often reported in post-COVID-19 syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that the Spike protein is released from cells during SARS-CoV-2 infection, reaching different tissues, including the CNS, even without the viral RNA. Here we demonstrate that the brain infusion of Spike protein in mice induces a late cognitive impact, recapitulating post-COVID-19 syndrome. We also showed that Spike protein induces cytokine upregulation and that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Synaptic pruning by microglia has been shown to underlie cognitive dysfunction in dementia and viral encephalitis. Complement component 1q (C1q) is known to be involved in the initial tagging of synapses, preceding synaptic engulfment by microglial cells. Accordingly, we found that blockage of soluble C1q could restore cognitive function in Spike protein-infused mice.