Abstract
SARS-CoV-2 is the virus that produces COVID-19 and Long Covid. Whereas COVID-19 is primarily an acute respiratory disease, Long Covid is a chronic condition with many symptoms likely mediated through the CNS, including brain fog, fatigue, and cognitive impairments. How a respiratory virus can produce a CNS disease is an important question, as is whether a sustained, Alzheimer's disease (AD)-like cognitive impairment will develop. We have postulated that SARS-CoV-2 and its viral attachment protein, S protein, can cross the blood-brain barrier (BBB) and that once in the CNS, can induce neuroinflammation, leading to cognitive impairments. We found that the S protein fragment S1 crosses the BBB as do a pseudotype virus expressing S1 and a virus like particle that expresses all 4 SARS-CoV-2 proteins. The pseudovirus once in the CNS invades microglia and increases both Iba1 and GFAP expression. S1 injected into the brains of young or aged CD-1 mice increases brain levels of only one cytokine: RANTES. Sex, age, and obesity are risk factors for COVID-19 and Long Covid, but did not modify the response of brain cytokines to S1. However, in the SAMP8 AD mouse model, several cytokines (RANTES, IL-12p(40), MIP-1 alpha, and MIP-1beta) were released from young mice brain. In aged SAMP8 mice, which display the AD phenotype, these cytokines were released more robustly than in young SAMP8 mice and eotaxin was additionally released. In conclusion, these results support that SARS-CoV-2 and the S1 protein cross the BBB to induce neuroinflammation.