BBB disruption is a disease-driving feature of several neurological disorders, including ALS, yet today no treatment exists to repair the BBB. Here, we screened the effect of a subcommissural organ-spondin-derived peptide (NX210c), known to promote functional recovery in several models of neurological disorders, on BBB integrity.Mouse endothelial cell (EC) monolayers and human BBBs (EC, astrocytes, pericytes) in static or microfluidic conditions, were treated with NX210c (1-100μM) or its vehicle. In mouse EC, NX210c induced a transient increase in occludin levels after 24h treatment (+37%, 100µM). Claudin-5 levels were also increased after 24h (+43%, 100µM) and 72h. Accordingly, NX210c decreased by half the permeability to a 40 kDa-dextran and increased transendothelial electrical resistance (TEER). In the human static BBB model, NX210c increased by 30% the TEER at 100µM after 5 days. NX210c also increased TEER in the human 3D dynamic BBB model at 100µM after 4h, and reduced the permeability to a 4 kDa-dextran.3- and 21-month-old mice were treated i.p. with NX210c (10mg/kg) or its vehicle for 5 days once a day and brains collected at day6. NX210c restored aging-induced reduction of claudin-5 and occludin levels in the cortex and hippocampus. This is in alignment with positive signals of BBB repair after repeated i.v. injections of NX210c in healthy elderly volunteers in a phase 1b trial, including a reduction of claudin-5 in the plasma.By repairing the BBB, NX210c may represent a disease-modifying treatment for several neurological disorders which will in turn reduce neurodegenerative processes and promote functional recovery.