Metabolic reprogramming is critical to microglial activation in Huntington’s disease
Abhishek Jauhari, Adam C. Monek, Olena S. Abakumova, Tanisha Singh, Sukhman Singh, Xiaomin Wang, Carley S. Clise, Diane L. Carlisle, Robert M. Friedlander
Abhishek Jauhari, Adam C. Monek, Olena S. Abakumova, Tanisha Singh, Sukhman Singh, Xiaomin Wang, Carley S. Clise, Diane L. Carlisle, Robert M. Friedlander
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Research Article Metabolism Neuroscience

Metabolic reprogramming is critical to microglial activation in Huntington’s disease

Abstract

Huntington’s disease (HD) is a fatal neurodegenerative disease caused by an expanded polyglutamine (CAG) repeat in the N-terminal of the huntingtin protein (HTT). Microglial activation and elevated proinflammatory cytokines are observed in HD brains, but the mechanisms regulating neuroinflammation and microglial activation are poorly understood. Metformin-mediated neuroprotection has been demonstrated in experimental models of neurodegeneration, including HD. We found that metformin inhibits mitochondrial DNA (mtDNA) release and subsequent neuroinflammation in the cortex and striatum of a mouse model of HD. Moreover, elevated proinflammatory cytokines and microglial activation are inhibited by metformin in HD transgenic mouse brains. Metformin reduced pathological microglial clusters and shifted toward a quiescent, homeostatic phenotype. Metformin improved aberrant immunometabolism in HD mouse brains and primary microglia. Mechanistically, we found that metformin regulates mitochondrial fission, reprograms deregulated metabolism in HD microglia, and controls microglial activation and inflammation in HD transgenic mice.

Authors

Abhishek Jauhari, Adam C. Monek, Olena S. Abakumova, Tanisha Singh, Sukhman Singh, Xiaomin Wang, Carley S. Clise, Diane L. Carlisle, Robert M. Friedlander

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Figure 6

Metformin reprograms microglial metabolism via mitochondrial fission.

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Metformin reprograms microglial metabolism via mitochondrial fission. (A...
(A) Schematic diagram of metformin treatment in WT and R6/2 mouse primary microglia. (B) qPCR analysis of proinflammatory and microglial activation marker mRNAs (IL6, IL1B, IL18, TNFA, CD68, and IRF7) in primary microglial cells isolated from WT (n = 5) and R6/2 (n = 4) mouse brains following treatment with metformin or vehicle. (C) Real-time oxygen consumption rate (OCR) measurements in WT and R6/2 primary microglia treated with or without metformin (25 μM) for 72 hours. Mitochondrial stress test was performed using sequential injections of oligomycin, FCCP, and rotenone/antimycin A (Rot/AA); OCR was normalized to nuclear staining. (D) Quantification of basal and maximal respiration from the same experiment. OCR was measured using a Seahorse XFe96 analyzer; WT, n = 5; R6/2, n = 4. (E and F) Representative immunoblot images (E) and their normalized quantification (F) showing expression of DRP1 (n = 3), phosphorylated DRP1, MFF, phosphorylated MFF, pro-IL1B, cleaved IL1B, and β-actin (n = 4) in primary microglia. Data in all panels are presented as mean ± SEM and were analyzed by 2-way ANOVA followed by Tukey’s test. *P < 0.05; **P < 0.01; ***P < 0.001.