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 1

Metformin regulates mtDNA release and subsequent inflammation in HD.

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Metformin regulates mtDNA release and subsequent inflammation in HD. (A)...
(A) Quantification of cytosolic mtDNA in WT and R6/2 cortex treated with or without metformin; n = 4 for vehicle and n = 5 for metformin group. (B) Quantification of cytosolic mtDNA in WT and R6/2 striatum treated with or without metformin; n = 4. (C) Heatmap showing qPCR-based mRNA expression of inflammatory, microglial activation, and synaptic genes in the cortex of WT and R6/2 mice, demonstrating that genes significantly upregulated in R6/2 mice were significantly downregulated following metformin treatment; n = 3–5. (D) Heatmap showing qPCR-based mRNA expression of inflammatory, microglial activation, and synaptic genes in the striatum of WT and R6/2 mice, demonstrating that genes significantly upregulated in R6/2 mice were significantly downregulated following metformin treatment. WT and R6/2 mice were treated with metformin 200 mg/kg body weight intraperitoneally. Data are represented as mean ± SEM. Individual data points in the graphs represent an independent biological sample; n = 3–5. Data were analyzed by 2-way ANOVA followed by Tukey’s test. ***P < 0.001.