Microglia are innate immune cells of the brain, analogous to macrophages elsewhere in the body. They attack pathogens, remove damaged cells, clear up debris, and assist in some aspects of the function of neural networks. With age, microglia become more prone to inflammatory behavior. Chronic, unresolved inflammation is harmful to tissue structure and function. Some of this is a maladaptive reaction to growing levels of molecular waste present in the brain, such as protein aggregates characteristic of neurodegenerative conditions, some the result of other processes of aging operating inside microglia, such as mitochondrial dysfunction.
Inhibiting CSF1R kills microglia (and macrophages), and there is a small molecule cancer drug that can achieve this in practice, called pexidartinib or PLX-3397. Clearance of microglia requires a much lower dose than is used in cancer patients, and so the side-effect profile is much more reasonable. The population of microglia and macrophages regenerates from progenitor populations within a few weeks following clearance, and in animal studies of neurodegeneration and brain aging this treatment has been shown to reduce the number of inflammatory microglia, reduce inflammation in the brain, and otherwise improve function. In today's open access paper, researchers try a lower dose and lesser degree of clearance of microglia, and still see benefits to cognitive function in aged mice.
Microglia depletion, followed by repopulation, improves cognitive functions in the aged mouse brain. However, even temporary ablation of microglia puts the brain at a high risk of infection. Hence, in the present work, we studied if the partial reduction of microglia with PLX3397 (pexidartinib), an inhibitor of the colony-stimulating factor 1 receptor (CSF1R), could bring similar benefits as reported for microglia ablation. Aged (two-years-old) mice were treated with PLX3397 for a total of 6 weeks, which reduced microglia numbers in the hippocampus and retrosplenial cortex (RSC) to the levels seen in young mice and resulted in layer-specific ablation in the expression of microglial complement protein C1q mediating synaptic remodeling.
This treatment boosted long-term potentiation in the CA1 region and improved performance in the hippocampus-dependent novel object location recognition task. Although PLX3397 treatment did not alter the number or total intensity of Wisteria floribunda agglutinin-positive perineuronal nets (PNNs) in the CA1 region of the hippocampus, it changed the fine structure of PNNs. It also elevated the expression of perisynaptic proteoglycan brevican, presynaptic vGluT1 at excitatory synapses, and vGAT in inhibitory synapses in the CA1 stratum radiatum. Thus, targeting the CSF1R may provide a safe and efficient strategy to boost synaptic and cognitive functions in the aged brain.
View the full article at FightAging
