• SARS-CoV-2 is known to bind to ACE2. ACE2 is upregulated in the human brain vasculature of hypertensive and dementia cases. • The SARS-CoV-2 spike protein does not acutely affect the viability of brain endothelial cells. • Blood-brain barrier function is negatively affected by SARS-CoV-2 spike protein subunits. • Brain endothelial cells show a distinct pro-inflammatory response when exposed to various SARS-CoV-2 spike protein subunits. • Mechanistically, barrier disruption may be explained by induction of members of the MMP family of proteins.