Here we will review data indicating that the interaction between TWEAK and Fn14 in the endothelial cell-BM-astrocyte interface regulates the function of the BBB following an ischemic/hypoxic injury, and that pharmacological inhibition of TWEAK-Fn14 is a promising target for the treatment of patients with neurological diseases that have a direct impact on the structure and function of the NVU. Here, TNFSF12 is linked to nervous system disorder.