SARS-CoV-2 has been shown to destabilize barrier function in both the brain and lung to increase pathological effects. The integrin α5β1 receptor is expressed on vascular endothelial cells during injury and in low oxygen environments and can cause decreased tight junction protein expression in vascular endothelial cells due to its physiological role in promoting angiogenesis. Previously, it has been shown that inhibition of α5β1 by the small peptide integrin inhibitor ATN-161 can reduce pathological outcomes in mouse brain endothelial (bEnd.3) cells in vitro during oxygen deprivation and has a protective effect in reducing pathology associated with SARS-CoV-2 infection in transgenic K18-hACE2 mice in vivo. Recently, a Mouse Adapted SARS-CoV-2 (MA10) has emerged which allows for infection in standard laboratory mice. In this work, I investigated the effect that SARS-CoV-2 (MA10) has on immune and neurovascular dysfunction and tested the hypothesis that ATN-161 can rescue barrier integrity and immune response in the brain. I first examined the effect that SARS-CoV-2 spike protein has on the expression of integrin α5β1and claudin-5 tight junction protein in bEnd.3 cells under hypoxic conditions. I then showed that SARS-CoV-2 (MA10) causes pronounced neuropathology in standard laboratory mice. Finally, I showed that ATN-161 restores tight junction loss and attenuates immune response as measured by pro-inflammatory IL-6 mRNA transcript levels in the brains of SARS-CoV-2 (MA10) infected mice in vivo. My findings suggest that the therapeutic application of ATN-161 may be useful in reducing SARS-CoV-2 associated barrier disruption and immune IL-6 levels in the brain, and explores a novel mechanism of action of ATN-161 involving serotonin signaling.