An Alternative to Clearance for Reduction of Activated Microglia in the Aging Brain
Microglia are innate immune cells of the central nervous system. Microglia in the aging brain respond to the age-damaged environment by becoming more activated, inflammatory, and ultimately senescent. They amplify the inflammatory environment, contributing further to damage and loss of function. One approach is to clear these cells, readily achieved using available CSF1R inhibitor drugs, after which a new population emerges that, for a time at last, is not overly activated and inflammatory. Here, researchers discuss a different approach to reducing microglial activation, without clearing the entire population of microglia, in the context of age-related blood-brain barrier dysfunction.
While it's well established that chronic mild hypoxia promotes a robust angiogenic response, we recently found that it also triggers transient blood-brain barrier (BBB) disruption, that is associated with aggregation and activation of microglia around the leaky blood vessels. Importantly, microglial depletion markedly enhanced vascular leak, demonstrating an important vasculo-protective function for microglia in maintaining BBB integrity. As a high integrity BBB is a critical determinant of cerebral health, yet evidence suggests that BBB integrity declines with age, we recently examined how aging influences both the extent of hypoxia-induced BBB disruption and the associated vasculo-protective function of microglia. This showed that compared to young (8-10 weeks) mice, the number of hypoxia-induced vascular leaks was greatly amplified (5-10 fold) in aged (20 months) mice in all regions of the brain examined.
When we analysed the impact of aging on microglia activity, we discovered an interesting paradox. On the one hand, microglia in aged brain were far more activated as assessed by morphological criteria and expression of activation markers such as Mac-1 and CD68, but on the other hand, they displayed a marked deficit in the ability to aggregate around leaky blood vessels. These findings are consistent with the work of others who showed microglia in aged brain are typically more activated than in young mice. Interestingly, microglia in the aged brain can be re-programmed by removing all microglia with the colony stimulating factor-1 receptor (CSF-1R) antagonist PLX5622, and then allowing the central nervous system to repopulate with new microglia displaying a younger phenotype. Notably, this approach was shown to reverse age-related cognitive decline, although vascular integrity was not examined.
In our study we took the simpler approach of reducing microglial activation state in the aged brain by treating mice with minocycline and this successfully reduced the number of hypoxia-induced vascular leaks. Based on these data, we proposed a biphasic relationship between microglial activation and vasculo-protection, such that microglia need to become activated to confer protection, but if they become too activated, as in the aged brain, this protection declines.