Exercise Beneficially Alters Polarization of Microglia in the Brain
Regular moderate exercise remains one of the most beneficial interventions when it comes to slowing the progression of degenerative aging, if balancing effect size against volume of supporting data. This isn't where we'd like to be! Biotechnology is capable of so very much more, but progress is slow, and robust assessment of new therapies across large populations slower still. Exercise introduces sweeping changes in cellular biochemistry and the function of higher level systems in the body, which makes it an ongoing challenge for the research community to understand exactly how it produces benefits. As is usually the case, there is a disconnect between (a) the data that can be connected on cellular biochemistry and (b) an assessment of health parameters. Joining the dots between the high level and the low level is a sizable project with no end in sight.
Microglia are innate immune cells resident in the brain, analogous to macrophages elsewhere in the body. Like macrophages, microglia adopt polarizations, defined packages of behaviors. An M1 microglia is pro-inflammatory, focused on chasing down pathogens. An M2 microglia is anti-inflammatory, focused on aiding in tissue regeneration and clearance of metabolic waste. Polarization is a useful concept, but the underlying range of behaviors across individual cells is more an analogue continuum from pro-inflammatory to anti-inflammatory, and the same for other behaviors, than a binary choice. Still, polarization can be influenced, and researchers are interested in finding ways to change microglia behavior in order to suppress inflammatory signaling and encourage tissue regeneration. As noted in today's open access paper, that exercise can affect polarization may lead to regulatory mechanisms that can be adjusted by other means.
Lifestyle changes including increased physical activity is an effective strategy for delaying the progression of neurodegenerative disease. Several studies have proposed a possible link between exercise training and cognitive improvement. We trained mice to run at increasing speed over 8 weeks which represents a typical in vivo model of physical activity. The principal findings of our study are 1) Exercise training improves cognitive function in AlCl3/D-galactose-treated mice and aging mice by reducing neuronal loss and neuroinflammation, and 2) Elevated levels of lactate in the brain attenuate this neuroinflammation by acting as an "accelerator" for the "lactate timer" in microglia by promoting transition to a reparative phenotype through Histone H3 Kla. Our results provide an extension to the beneficial effects of exercise training beyond strengthening skeletal muscle, and further confirm that exercise training improves cognitive function and reverses neuronal loss in the brain of AD-like mice.
Other studies have attributed the beneficial effects of exercise to lactate. For example, lactate partially mediates the effect of physical exercise on neurogenesis in a MCT2-dependent manner. Subcutaneous injection of lactate lead to an increase in blood lactate levels similar to exercise and increases brain VEGF protein. These studies provide a preliminary link between exercise, lactate, and cognitive function. Although studies demonstrated an important role of lactate in physiological function in neurons and astrocytes, there has been little empirical investigation on microglia. Over the past thirty years, microglia are traditionally described as two states, resting and activated. The reactive gliosis observed in Alzheimer's disease histopathology reflects an abnormal morphology and proliferation of microglia. Once overactivated microglia release a wide range of inflammatory and bioactive molecules which impose negative impacts on neurons. Extensive activation of microglia was detected in our AD mice and may contribute to the observed cognitive impairment.
Both running training and exogenous lactate treatment inhibited the hyperactivation of microglia in AD-like mice and increased the number of anti-inflammatory/reparative microglia. In vitro experiments in microglia confirmed that lactate treatment significantly increases the expression of repair genes, indicating that lactate may promote a shift in balance from damaging to reparative microglia.