Fight Aging!

Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body, involved in tissue maintenance as well as defense against pathogens. Like macrophages, microglia adopt packages of behaviors called polarizations. The two of greatest interest are M1, inflammatory and hunting down pathogens and errant cells, versus M2, anti-inflammatory and engaging in tissue maintenance. An increase in inflammatory microglia, a maladaptive response of the innate immune system to molecular damage characteristic of aging, is thought to contribute to the aging of the brain.

There are a few ways to selectively destroy microglia, one of which is use of pexidartinib, PLX3397. This drug inhibits CSF1R activity, which causes microglia to die. The population of microglia then recovers within a few weeks after use of the drug ceases. The newly created microglia tend to exhibit fewer of the maladaptive traits of the old, cleared population, such as overly inflammatory behavior. This has allowed researchers to test microglial clearance as a basis for therapy in animal models of various neurodegenerative conditions. So far the results seem generally positive, but in today's open access paper, results in a mouse model of Alzheimer's disease are not as hoped for.

Partial microglial depletion and repopulation exert subtle but differential effects on amyloid pathology at different disease stages

Microglia are the resident innate immune cells of the central nervous system (CNS). They play a key role in neurodevelopment and plasticity, as well as in the pathogenesis of a wide array of neurodevelopmental and neurodegenerative disorders. In Alzheimer's disease (AD), genetic risk factors are disproportionately linked to immune receptors expressed by microglia, positioning these cells as important targets for disease-modifying therapies. However, in the chronic neuroinflammatory environment in AD, the role of microglia is complex. In fact, removal of microglia in AD mouse models via inhibition of colony-stimulating factor 1 receptor (CSF1R), which is critical for microglial survival and proliferation, reduced plaque formation when administered early but not during advanced amyloid pathology, which is more translationally relevant. Additionally, while some studies have shown that late loss of microglia improved learning and memory, and lessened neuronal loss, others demonstrated that it also increased plaque-associated neuritic damage.

Rather than removing microglia, renewing them through depletion followed by repopulation presents another exciting strategy. Adult microglia are capable of rapidly replenishing their niche within 1 week after removal of CSF1R inhibitor, restoring their morphology and physiological functions. In several injury models and in aging, repopulated microglia have been shown to be beneficial in promoting brain recovery and reversing age-related neuronal deficits. However, in the context of AD, we previously found no beneficial effects of microglial repopulation on either amyloid pathology nor cognitive function in aged transgenic mice harboring both amyloid and tau pathology. On the other hand, early microglia renewal was suggested to partially rescue cognitive deficits by restoring the microglial homeostatic phenotype.

Here, we sought to delineate the dynamic effects of microglial depletion followed by repopulation on microglia function and amyloid-β plaque burden during different stages of amyloid pathology. We administered the CSF1R inhibitor PLX3397 (hereafter referred to as PLX) in 5xFAD mice and tracked microglia-plaque dynamics with in vivo imaging. We revealed a transient improvement in plaque burden that occurred during either the depletion or repopulation period depending on the animal's age. Interestingly, while the improvement in plaque load did not persist long-term, repopulated microglia during mid-to-late pathology stages appeared to retain or increase their sensitivity to noradrenergic signaling, which is largely thought to be anti-inflammatory.