<p>Building on our previous finding that a small fibrinogen peptide inhibits microglial repair of the hypoxia-disrupted blood-brain barrier (BBB), we directly evaluated the importance of fibrinogen in this process by studying these events in fibrinogen knockout (KO) mice. While young (4 months old) fibrinogen KO mice were still capable of mediating a vasculo-protective response to chronic mild hypoxia (CMH; 8% O₂), the extent of vascular leak in these mice was much greater than wild-type (WT) mice. Consistent with this, fibrinogen KO mice displayed greatly reduced levels of hypoxia-induced microglial activation, proliferation, and aggregation around leaky blood vessels. Notably, defects in fibrinogen KO mice became more pronounced with age such that by 8-months old, a large fraction (3/8) of fibrinogen KO mice failed to survive 4 days CMH, and those that survived showed much greater loss of myelin and neurons compared to WT. Furthermore, under normoxic conditions, microglia in middle-aged (13 months old) fibrinogen KO mice were significantly less activated compared to WT, suggesting that slow fibrinogen leak across the age-weakened BBB might explain why microglia are more activated in aged mice. Finally, in vitro studies revealed that microglia readily attach to fibrinogen and that compared to other pro-adhesive ECM proteins such as fibronectin, fibrinogen promotes morphological transition into a polarized phenotype capable of greater levels of migration. Together, these observations demonstrate the importance of fibrinogen in promoting an effective microglial vasculo-protective response and suggest that pharmacological manipulation of fibrinogen-microglial interactions in the aged brain could hold therapeutic promise in the prevention or treatment of vascular dementia.</p>