Metabolic reprogramming and signalling networks in microglial activation: Implications for neurodegeneration

Microglia, the brain's innate immune cells, undergo a complex activation process characterized by metabolic reprogramming and inflammatory signalling that transcends the classical M1/M2 polarization framework. Recent advances in single-cell technologies have unveiled remarkable microglial heterogeneity, including the emergence of disease-associated microglia (DAM), which play critical roles in neurodegeneration. This study synthesizes recent findings from single-cell transcriptomics, spatial proteomics, and metabolomics to provide an integrated perspective on microglial activation. We focus on the interplay between key metabolic pathways, including glycolysis, the pentose phosphate pathway, and oxidative phosphorylation, as well as inflammatory signalling networks such as NF-κB, HIF-1α, and JAK/STAT, across diverse neurodegenerative conditions. Our synthesis reveals that microglial activation is driven by coordinated metabolic and inflammatory reprogramming, forming self-reinforcing cycles that sustain neuroinflammation. Disease-associated microglia display unique transcriptional profiles distinct from traditional polarization states, with notable regional and sex-specific variations in activation patterns. Crucially, crosstalk between the HIF-1α and NF-κB pathways modulated by metabolic sensors like CARKL underpins persistent inflammatory responses. Additionally, researchers have identified novel neuroprotective mechanisms, including mitochondrial transfer from microglia to neurons via tunneling nanotubes. Importantly, chronic neuroinflammation in neurodegenerative diseases appears to arise not from persistent microglial activation per se, but from failures in inflammatory resolution. Viewing microglial activation as an integrated metabolic-inflammatory network highlights new therapeutic avenues. While metabolic inhibitors hold conceptual promise, their clinical infeasibility necessitates a paradigm shift toward TREM2 immunomodulators and resolution agonizts with established human safety profiles. Strategies targeting metabolic reprogramming, enhancing resolution pathways, and promoting beneficial microglial-neuronal interactions hold promise for treating neurodegenerative disorders. Furthermore, identifying biomarkers of microglial activation states may enable the development of personalized therapeutic approaches.