Exaggerated hypoxic vascular breakdown in aged brain due to reduced microglial vasculo‐protection

In a recent study of young mice, we showed that chronic mild hypoxia (CMH, 8% O 2 ) triggers transient blood–brain barrier (BBB) disruption, and that microglia play an important vasculo‐protective function in maintaining BBB integrity. As hypoxia is a common component of many age‐related diseases, here we extended these studies to aged mice and found that hypoxia‐induced vascular leak was greatly amplified (5‐fold to 10‐fold) in aged mice, being particularly high in the olfactory bulb and midbrain. While aged mice showed no obvious difference in the early stages of hypoxic angiogenic remodeling, the compensatory increase in vascularity and vessel maturation was significantly delayed. Compared with young brain, microglia in the normoxic aged brain were markedly activated, and this was further increased under hypoxic conditions, but paradoxically, this correlated with reduced vasculo‐protection. Microglial depletion studies showed that microglial still play an important vasculo‐protective role in aged brain, but interestingly, partial attenuation of microglial activation with minocycline resulted in fewer vascular leaks and reduced loss of endothelial tight junction proteins. Taken together, these findings suggest that increased BBB disruption in hypoxic aged mice can be explained both by a delayed vascular remodeling response and reduced microglial vasculo‐protection. Importantly, they show that overly activated microglia in the aged brain are less effective at maintaining vascular integrity, though this can be improved by reducing microglial activation with minocycline, suggesting therapeutic potential for enhancing BBB integrity in the hypoxia‐predisposed elderly population.