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 2

Metformin inhibits proinflammatory microglial activation in HD.

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Metformin inhibits proinflammatory microglial activation in HD. (A) Repr...
(A) Representative immunofluorescence images stained with IBA1 (microglia marker), CD16 (proinflammatory microglia marker), and DAPI (nuclear marker) in WT and R6/2 striatum treated with metformin (200 mg/kg body weight) or vehicle. Scale bars: 50 μm. (B) Quantification of immunofluorescence in percentage of microglial cells showing CD16 signals per view fields in WT and R6/2 striatum treated with metformin (200 mg/kg body weight) or vehicle; n = 3. Twelve images per animal. (C) Representative immunoblot images of ASC, HS1, CD68, CD86, iNOS, and β-actin in WT and R6/2 striatum treated with metformin (200 mg/kg body weight) or vehicle. (D) Normalized quantification of immunoblots of ASC, HS1, CD68, CD86, and iNOS shown in C. Data are represented as mean ± SEM. Individual data points in the graphs represent an independent biological sample. Data were analyzed by 2-way ANOVA followed by Tukey’s test. *P < 0.05; **P < 0.01; ***P < 0.001.