Replacement of Aged Microglia Partially Reverses Cognitive Decline in Mice

Researchers here report on a compelling demonstration that shows the degree to which dysfunctional microglia contribute to age-related neurodegeneration. The scientists use a pharmacological approach to greatly deplete the microglial population and then allow it to recover naturally. The influx of new microglia improves many aspects of brain function, though interestingly this procedure doesn't appear to affect the inflammatory status of brain tissue. Most neurodegenerative conditions are thought to be driven to some degree by inflammation, while the data here suggests that the activities of glial cells that support neuronal function are not to be neglected.

The data also suggests that inflammation is a reaction to the state of brain tissue, rather than something that arises from intrinsic issues within glial cells. That conclusion is contradicted by other recent research in which senescent glial cells are shown to definitively contribute to the pathology of neurodegenerative disease. Perhaps the resolution of this contradiction is that senescent glial cells are resistant to depletion via the methodology used here, but that is pure speculation on my part.

Microglia are the primary immune cells of the central nervous system (CNS), where they act as responders in the event of infection or injury. Microglia "at rest" are highly dynamic cells, constantly extending and retracting their processes to sample the local environment. Beyond immune function, studies implicate microglia in maintaining tissue homeostasis and synaptic connectivity. In neurodegenerative disease or following traumatic brain injury, microglia can assume long-lasting changes in morphology, densities, gene expression, and cytokine/chemokine production. Studies have indicated that these signals, when persistent in the brain, can lead to further harm.

Microglia are critically dependent upon signaling through the colony-stimulating factor 1 receptor (CSF1R) for their survival. We identified several orally bioavailable CSF1R inhibitors that noninvasively cross the blood-brain barrier, leading to brain-wide microglial elimination within days, which continues for as long as CSF1R inhibition is present. In particular, removal of CSF1R inhibition stimulates the rapid repopulation of the entire brain with new microglial cells, effectively replacing the entire microglial tissue. This process takes approximately 14-21 days to complete; thereafter, the new microglia are virtually indistinguishable from the resident microglia.

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.


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