Abstract
Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.
Highlights
Microglial activation is a hallmark of aging and studies have shown that microglial phenotype and function are altered in the aged brain [reviewed in (Mosher & Wyss‐Coray, 2014)]
To explore how the replacement of aged microglia with new cells affects and shapes the resultant tissue, we employed a method of colony‐stimulating factor 1 receptor (CSF1R) inhibitor‐induced microglial elimination and repopulation
Measurements of the chow‐administered PLX5622 in both plasma and brain tissue revealed a comparable reduction in inhibitor levels in aged mice, reflecting either reduced chow‐intake with aging, an increased metabolism and excretion of the compound, or an altered sensitivity of microglia with age
Summary
These authors contributed to this study. Microglia are the primary immune cells of the central nervous system (CNS), where they act as responders in the event of infection or. Microglia undergo marked phenotypic and functional changes compared to the adult brain, including increased cell numbers, dystrophic morphology, impaired phagocytosis, reduced motility, exaggerated response to inflammatory stimuli [reviewed in Mosher and Wyss‐Coray (2014)], as well as altered gene expression (Galatro et al, 2017; Grabert et al, 2016; Soreq, Rose, Soreq, Hardy, & Ule, 2017) These microglia are often described as “primed” or “senescent,” and recent studies suggest that these cells may contribute to age‐related cognitive impairments and confer susceptibility to neurodegenerative disease (Blank & Prinz, 2013; Niraula, Sheridan, & Godbout, 2017; Norden, Muccigrosso, & Godbout, 2015). This study demonstrates that broad reversals in many age‐related changes in the brain can be achieved utilizing microglial repopulation, including improvements in cognition, as well as neuronal/synaptic‐related gene expression, structure, and function
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