INNOVAPATH · Jun 22, 2026
Microglial Metabolic Reprogramming: The Missing Link in Chronic Neurodegeneration
By Maqsood R, Mushtaq A, Nawaz K et al.
Background: Microglial activation and sustained neuroinflammation are central features of chronic neurodegenerative diseases. Emerging evidence indicates that microglial function is tightly linked to intracellular metabolic state, with shifts between oxidative phosphorylation (OXPHOS) and glycolysis shaping inflammatory output, phagocytosis, and neurotoxicity. Objective: To synthesize mechanistic, translational, and disease-specific evidence that positions microglial metabolic reprogramming as a key driver and potential therapeutic target in chronic neurodegeneration. Methods: Narrative synthesis of preclinical and clinical studies addressing microglial metabolism, mitochondrial dysfunction, inflammasome activation, and immunometabolic interventions. Findings: Pro-inflammatory stimuli (LPS, amyloid-β, α-synuclein) induce glycolytic reprogramming in microglia, accompanied by mitochondrial dysfunction, ROS generation, and NLRP3 inflammasome activation (3,6,9). Disease-specific evidence links these metabolic shifts to impaired debris clearance and sustained cytokine release in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and ALS (8,10–13). Aging-associated metabolic drift primes microglia toward inflammatory phenotypes (14). Interventions targeting glycolysis, AMPK activation, or NLRP3 show preclinical promise (3,6,16). Conclusion: Microglial immunometabolism provides a mechanistic bridge between chronic inflammation and neurodegeneration. Precision metabolic modulation of microglia — recalibrating rather than suppressing activity — is a promising translational strategy warranting biomarker-guided clinical evaluation.