ena-STUDY-SEOUL NATIONAL UNIVERSITY-09-05-2019-11:58:43:636-883
A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer's disease
Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, it is still unclear how microglia are activated and contribute to the pathogenesis of AD. Here, using metabolic and transcriptomic profiling of microglia in vitro and in vivo, we found that exposure to amyloid-ß (Aß) peptides triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. This metabolic reprogramming was dependent on the mTOR (mammalian target of rapamycin)/HIF-1a (hypoxia-inducible factor-1a) pathway. However, once activated, microglia reached a chronic tolerant phase as a result of broad defects in energy metabolisms and subsequently diminished immune responses, including cytokine release, cellular recruitment, and phagocytosis. Using genome-wide RNA sequencing of microglia ex vivo and intravital multiphoton microscopy techniques, we further identified metabolically defective tolerant microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting by treatment with recombinant interferon-? (IFN-?) reversed the defective glycolytic metabolism and altered inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Our findings reveal that metabolic reprogramming is a crucial mechanism for microglial function in AD, and suggest that modulating cellular metabolism might be a new therapeutic strategy for AD.
Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, it is still unclear how microglia are activated and contribute to the pathogenesis of AD. Here, using metabolic and transcriptomic profiling of microglia in vitro and in vivo, we found that exposure to amyloid-ß (Aß) peptides triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. This metabolic reprogramming was dependent on the mTOR (mammalian target of rapamycin)/HIF-1a (hypoxia-inducible factor-1a) pathway. However, once activated, microglia reached a chronic tolerant phase as a result of broad defects in energy metabolisms and subsequently diminished immune responses, including cytokine release, cellular recruitment, and phagocytosis. Using genome-wide RNA sequencing of microglia ex vivo and intravital multiphoton microscopy techniques, we further identified metabolically defective tolerant microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting by treatment with recombinant interferon-? (IFN-?) reversed the defective glycolytic metabolism and altered inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Our findings reveal that metabolic reprogramming is a crucial mechanism for microglial function in AD, and suggest that modulating cellular metabolism might be a new therapeutic strategy for AD.