Poster abstracts

Poster number 78 submitted by Shane ONeil

Microglia are Extrinsically Primed by the Aged Microenvironment

Shane M. ONeil (Neuroscience Graduate Program), Kristina G. Witcher (Neuroscience Graduate Program), Daniel B. McKim (Department of Neuroscience), Jonathan P. Godbout (Department of Neuroscience, Institute for Behavioral Medicine Research, Chronic Brain Injury Program)

Abstract:
Microglia, the innate immune cells of the central nervous system (CNS), have limited turnover throughout the lifespan, leaving them susceptible to age-associated dysfunction. Indeed, microglia develop a pro-inflammatory, “primed” profile with age. Moreover, peripheral lipopolysaccharide (LPS) causes an exaggerated neuroinflammatory response mediated by primed microglia in the aged brain. Recent studies show microglia can be depleted without significant complications. Therefore, we hypothesized depletion of microglia in the aged brain would result in repopulation with new, unprimed microglia. Here we provide evidence that microglia in the aged brain repopulate as new microglia no longer burdened with lipofuscin. Moreover, age-associated increases in CD68 expression were reversed by microglial repopulation. Microglia-specific RNA sequencing revealed 511 differentially expressed genes with age. Of these, 117 genes were reversed by microglial repopulation. Nevertheless, LPS challenge still induced an exaggerated inflammatory response in the aged brain compared to adults. RNA sequencing of whole-brain tissue revealed an age-induced inflammatory signature, including reactive astrocytes, that was not restored by microglial repopulation. Furthermore, the microenvironment of the aged brain produced soluble factors that influenced developing microglia ex vivo and induced a profile primed to LPS challenge. These data indicate the microenvironment of the aged brain promotes microglial priming despite repopulation of new microglia. Taken together, aged microglia can proliferate and repopulate the CNS, but the resulting microglia still adopt a pro-inflammatory profile characteristic of aging. Additionally, repopulating microglia have significantly lower levels of CD68 and lipofuscin, a major source of reactive oxygen species and metabolic dysregulation, indicating potential functional benefits of microglial repopulation despite a continuing pro-inflammatory phenotype.

Keywords: microglia, aging, priming