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A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease
Sung Hoon Baik1, Seokjo Kang1, Woochan Lee2
1Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul 03080, South Korea.
Abstract:
Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using metabolic profiling, we found that exposure to amyloid-β triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis. It was dependent on the mTOR-HIF-1α 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 secretion and phagocytosis. Using genome-wide RNA sequencing and multiphoton microscopy techniques, we further identified metabolically defective microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting with recombinant interferon-γ treatment reversed the defective glycolytic metabolism and inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Collectively, metabolic reprogramming is crucial for microglial functions in AD, and modulating metabolism might be a new therapeutic strategy for AD.
Insights
Microglia in Alzheimer's disease (AD) shift metabolism, initially boosting inflammation but later becoming defective. Metabolic interventions can restore microglial function and reduce AD pathology.
Area of Science:
- Neuroimmunology
- Metabolic pathways in neurodegeneration
- Alzheimer's disease pathogenesis
Background:
- Reactive microglia are a hallmark of Alzheimer's disease (AD), but their precise role remains elusive.
- Understanding microglial function is critical for developing effective AD therapies.
Purpose of the Study:
- To investigate the metabolic changes in microglia during Alzheimer's disease progression.
- To explore the impact of metabolic reprogramming on microglial immune responses in AD.
- To evaluate the therapeutic potential of metabolic modulation for AD treatment.
Main Methods:
- Metabolic profiling and genome-wide RNA sequencing were employed.
- Multiphoton microscopy was used to visualize microglial activity in AD mouse models (5XFAD).
- Intervention with recombinant interferon-gamma was tested to assess metabolic and functional recovery.
Main Results:
- Amyloid-beta exposure induced acute microglial inflammation via mTOR-HIF-1α-dependent metabolic reprogramming (oxidative phosphorylation to glycolysis).
- Chronic activation led to metabolic defects and impaired microglial immune functions (cytokine secretion, phagocytosis) in 5XFAD mice.
- Metabolic boosting with interferon-gamma reversed glycolytic defects and enhanced microglial inflammatory functions, mitigating AD pathology.
Conclusions:
- Microglial metabolic reprogramming is a key factor in Alzheimer's disease pathogenesis.
- Defective microglial metabolism contributes to diminished immune responses in chronic AD.
- Targeting microglial metabolism represents a promising therapeutic strategy for Alzheimer's disease.