The protective role of microglia in preventing hypoxic disruption of blood-brain barrier integrity and VCID

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PROJECT SUMMARY/ABSTRACT Dementia is a major health problem in the United States. Vascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer’s disease (AD) but despite the massive impact of VCID in the expanding elderly population, its pathogenesis is still only poorly understood. The consensus is that in the aging brain, particularly on a background of hypertension, blood vessels undergo degenerative changes, resulting in loss of blood-brain barrier (BBB) integrity and increased vascular resistance, which together, lead to cerebral hypoperfusion, neuronal damage and cognitive decline. Recently, we described a novel role for microglia in the maintenance of vascular integrity. We demonstrated that chronic mild hypoxia (CMH; 8% O2) induces transient vascular leak in spinal cord blood vessels in young (10 weeks old) mice, that is associated with microglial activation and clustering around leaky blood vessels. Interestingly, microglial depletion profoundly increased vascular leak and this was associated with astrocyte-vascular uncoupling and loss of vascular tight junction proteins, suggesting that microglia play an important protective role in maintaining vascular integrity in the spinal cord. We have since found that CMH also triggers vascular leak in the brain and that microglial depletion exacerbates this leak. Strikingly, in aged (20 months old) mice, the extent of hypoxic-induced cerebrovascular disruption is greatly enhanced, as shown by increased vascular leak and the emergence of microhemorrhages, though the impact of microglial depletion in aged mice has yet to be addressed. Together, our data suggests that microglia play an important vasculoprotective role in young mice, but this mechanism may be less effective in the aged brain. Taken with the observation that aging induces the appearance of a “primed”, pro-inflammatory, destructive microglial phenotype, we hypothesize that: (i) mild hypoxia triggers vascular leak and microhemorrhage in the brain, resulting in neuronal damage and cognitive decline, (ii) vascular disruption is worse in the aged and the hypertensive, (iii) microglia play an important vasculoprotective role in stabilizing the BBB, but this declines with age, and (iv) repopulating the aged brain with young microglia or attenuation of microglial activation state, could stabilize the BBB and reduce cognitive impairment. To investigate these hypotheses, we propose three specific aims: (1) characterize hypoxia-induced vascular leak in the brain and define how this is influenced by age, gender, severity of hypoxia, hypertension and brain region, (2) define the contribution of microglia in preventing hypoxia-induced cerebrovascular leak in young and aged mice, and (3) demonstrate that hypoxia-induced BBB disruption and cognitive impairment are reduced by repopulating the aged brain with “young” microglia or by attenuating microglial activation state. These studies will provide important insight into the link between hypoxic exposure, BBB disruption, neuronal damage and cognitive decline, and inform on the therapeutic potential of manipulating microglial behavior in the aged brain to restore vasculoprotective function.