Partially Reversing Cognitive Decline

Influx of new microglia was observed to improved many aspects of brain function, although the procedure did not appear to affect inflammation status of the brain which most neurodegenerative conditions are thought to be driven to some degree by.

This data suggests activities of glial cells supporting neuronal function are not to be neglected; and inflammation is a reaction state of the brain rather than something that arises from intrinsic issues with glial cells  in contradiction of other research that suggests glial cells contribute to the pathology of neurodegenerative disease; resolution to the contradiction may be that senescent glial cells are resistant to depletion via methodology used here.

Microglia are primary immune cells of the central nervous system acting as responders in event of infection or injury. At rest microglia are dynamic cells constantly extending and retracting processes to sample local environments. Microglia are implicated in studies to help in maintaining tissue homeostasis and synaptic connectivity. Microglia can assume long lasting changes in morphology, densities, gene expression, and cytokine production following traumatic brain injury or in neurodegenerative disease. Studies suggest these signals when persistent in the brain can lead to further harm.

Microglia are dependent upon signaling through CSF1R for their survival. Several orally bioavailable CSF1R inhibitors were identified that noninvasively cross the blood brain barrier leading to brain wide microglial elimination within a matter of days continuing as long as the inhibition is present. Removal of CSF1R inhibition stimulates rapid repopulation of new microglial cells within the entire brain which effectively replaces the entire microglial tissue. The new microglia are virtually indistinguishable from resident microglia from this process that take approximately 14 to 21 days to complete.

Replacement of resident microglia in aged mice improved spatial memory and restored physical microglia tissue characteristic to that found in younger animals within 28 days of repopulation. Inflammation related gene expression was not broadly altered by repopulation or response to immune challenges; rather repopulation resulted in reversal of age related changes in neuronal gene expression which included expression of genes associated with actin cytoskeleton remodeling and synaptogenesis.

Changes in hippocampal neuronal complexity that are age related were reversed with microglial elimination and repopulation, elimination increased neurogenesis and dendritic spine densities. Changes were accompanied by full rescue of age induced deficits in long term potentiation with microglial repopulation. Researchers suggest finding show that key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.