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Cell Metab. 2019 Sep 3;30(3):493-507.e6. doi: 10.1016/j.cmet.2019.06.005. Epub 2019 Jun 27.

A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease.

Author information

1
Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul 03080, South Korea.
2
Department of Biochemistry and Molecular Biology, Seoul National University, College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul 03080, South Korea.
3
Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul 03080, South Korea. Electronic address: inhee@snu.ac.kr.

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.

KEYWORDS:

Alzheimer's disease; HIF-1α; IFN-γ; OXPHOS; aerobic glycolysis; amyloid-β; mTOR; microglia

PMID:
31257151
DOI:
10.1016/j.cmet.2019.06.005

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