Glycolytic metabolism supports microglia training during age-related neurodegeneration

Glucose is a major energy source for the brain, necessary to preserve proper neurophysiological functions; aberrant glucose metabolism in the brain has been documented in chronic neurodegenerative pathologies. In addition, glucose-dependent metabolic pathways, including substrates of the Krebs cycle, are involved in peripheral and central innate immune activation through a molecular program known as trained immunity. Notably, it seems that defective glucose metabolism favors trained immunity in the brain, leading to neuronal damage and neurodegeneration. In addition, defective glucose metabolism in the brain correlates with a positive proinflammatory profile and microglia activation, as was found in postmortem samples of neurodegenerative pathologies. We hypothesized that fluctuations in glucose supply or metabolism in the brain during aging may alter microglial training, turning these cells to unresponsive or overresponsive to a challenge during age-related neurodegeneration. This review will cover the most significant advances in glucose-dependent metabolic pathways that favor innate trained immunity of microglia and their contribution to neurodegeneration.