Here, we used the K18 hACE2 transgenic mouse COVID-19 preclinical model [28] to assess microglial NLRP3 inflammasome expression in the brain upon SARS-CoV-2 infection, and a human monocyte-derived microglia (MDMi) cellular model to assess inflammasome activation in response to SARS-CoV-2 and its spike protein, and the consequences of this exposure in the presence of α-synuclein protein aggregate fibrils. This evidence concerns the gene NLRP3 and COVID-19.