Microglia-Specific Metabolic Changes in Neurodegeneration

Abstract

The high energetic demand of the brain deems this organ rather sensitive to changes in energy supply. Therefore, even minor alterations in energy metabolism may underlie detrimental disturbances in brain function, contributing to the generation and progression of neurodegenerative diseases. Considerable evidence supports the key role of deficits in cerebral energy metabolism, particularly hypometabolism of glucose and mitochondrial dysfunction, in the pathophysiology of brain disorders. Major breakthroughs in the field of bioenergetics and neurodegeneration have been achieved through the use of in vitro and in vivo models of disease as well as sophisticated neuroimaging techniques in patients, yet these have been mainly focused on neuron and astrocyte function. Remarkably, the subcellular metabolic mechanisms linked to neurodegeneration that operate in other crucial brain cell types such as microglia have remain obscured, although they are beginning to be unraveled. Microglia, the brain-resident immune sentinels, perform a diverse range of functions that require a high-energy expenditure, namely, their role in brain development, maintenance of the neural environment, response to injury and infection, and activation of repair programs. Interestingly, another key mechanism underlying several neurodegenerative diseases is neuroinflammation, which can be associated with chronic microglia activation. Considering that many brain disorders are accompanied by changes in brain energy metabolism and sustained inflammation, and that energy metabolism has a strong influence on the inflammatory responses of microglia, the emerging significance of microglial energy metabolism in neurodegeneration is highlighted in this review.

Microglial Activation in the Retina of a Triple-Transgenic Alzheimer’s Disease Mouse Model (3xTg-AD)

“…There is increasing evidence that energy metabolism and inflammation could be related and that mitochondrial energy could play an important role [50]. During the progression of AD, the microglia may initially assume a useful role to subsequently adopt a dysfunctional phenotype [51]. Thus, acute microglial activation leads to a decrease in the accumulation of Aβ by increasing its phagocytosis [41].…”

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

“…Another issue to be solved is how microglial energy production is regulated in the light of physiological and pathophysiological aspects. 179,180 Namely, microglia can be ameboid in shape and can travel upon various stimulations. The physical movement of cells requires more energy than that of cells in a quiescent state.…”

Metabolic Reprograming of Microglia in the Regulation of the Innate Inflammatory Response

“…It has been proposed that glucose metabolism exerts transcriptional control over microglial activation, and that the homeostatic phenotype of (cultured) microglia preferentially utilize oxidative metabolism (23)(24)(25)(26). An essential fuel for microglia is glucose, which enters the cell through different transporters (GLUTs) (27). Microglia predominantly express GLUT3 (28) and the fructose transporter GLUT5 (29,30), but under inflammatory conditions, GLUT1 expression is upregulated to increase glucose uptake and promote glycolysis (31).…”