Abstract # 2060 Microglia are extrinsically primed by the aged microenvironment

Abstract

Microglia are responsible for propagating inflammatory signals from the periphery to the brain, where they drive the behavioral sickness response. With normal aging, these cells develop a pro-inflammatory, “primed” profile with increased expression of inflammatory mediators. A critical question is if this priming can be reversed. CSF1R antagonism results in elimination of microglia in the adult brain followed by rapid repopulation. Therefore, we hypothesized CSF1R antagonist-mediated microglial depletion in the aged brain would result in repopulation of new, unprimed microglia. Here we provide evidence that microglia in adult and aged mice were robustly eliminated following oral administration of CSF1R antagonist PLX5622. When antagonism was stopped, microglia repopulated the adult and aged brain at the same rate and efficiency with new cells no longer burdened with lipofuscin, the hallmark lipid debris of aging. However, RNA-Seq analysis of FACS-sorted microglia revealed these new microglia had the same primed mRNA profile. Moreover, RNA-Seq analysis of the brain microenvironment provided evidence of astrogliosis in aged mice independent of microglial depletion/repopulation. Lastly, peripheral immune challenge still caused an exaggerated microglial inflammatory response in the aged brain with prolonged behavioral deficits. These data are interpreted to indicate the microenvironment of the aged brain significantly influences the profile of repopulating/proliferating microglia. Taken together, aged microglia proliferate and repopulate the CNS, but the repopulating microglia still adopt a pro-inflammatory profile characteristic of aging.