Microglia: Metabolic Adaptation in Neurodegeneration

Microglia, the brain’s primary innate immune cells, are metabolically dynamic cells whose functional states, from homeostatic surveillance to disease-associated phagocytosis, lipid droplet accumulation, and stress-induced neurotoxicity, are governed by distinct metabolic programs. Neurodegenerative stressors, including misfolded protein accumulation, oxidative stress, mitochondrial dysfunction, and sustained inflammation, initially trigger adaptive metabolic reprogramming of glycolysis, the tricarboxylic acid cycle, and amino acid and lipid pathways. Under chronic stimuli, these same shifts become maladaptive, impairing microglial phagocytosis, promoting lipid accumulation, and driving the secretion of neurotoxic lipid species. A unifying theme emerging across metabolic pathways is that the intermediates produced under stress, lactate, succinate, ceramide, acetyl-CoA, and α-ketoglutarate, do not merely reflect cellular state but actively reshape it through epigenetic modification of histones and DNA. In this review, we examine how each major metabolic pathway responds to acute and chronic neurodegeneration-associated stress in microglia, highlight where epigenetic mechanisms convert transient metabolic shifts into durable changes in microglial identity, and identify genetic risk factors that encode metabolic vulnerability in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease.