Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Physician-Scientist Development
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • In-Press Preview
    • Resource and Technical Advances
    • Clinical Research and Public Health
    • Research Letters
    • Editorials
    • Perspectives
    • Physician-Scientist Development
    • Reviews
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Resource and Technical Advances
  • Clinical Research and Public Health
  • Research Letters
  • Editorials
  • Perspectives
  • Physician-Scientist Development
  • Reviews
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
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
View: Text | PDF
Research Article Metabolism Neuroscience

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

  • Text
  • PDF
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

×

Figure 3

Metformin regulates microglial ramification in HD.

Options: View larger image (or click on image) Download as PowerPoint
Metformin regulates microglial ramification in HD.
(A–D) Representative ...
(A–D) Representative images of microglial morphology traced with NeuronJ of ImageJ from the striatum of WT brain (A), striatum of R6/2 brain (B), striatum of WT brain treated with metformin (C), and striatum of R6/2 brain treated with metformin (D). Note that microglial cells from untreated R6/2 mice display shorter processes and diminished ramification of processes (B), whereas microglia from metformin-treated R6/2 mice show longer and highly ramified processes (D). Scale bars: 10 μm. (E) Quantification of average area occupied by individual microglia (in μm2) in the striatum of WT and R6/2 mice treated with metformin or vehicle. (F) Quantification of total process length by individual microglia (in μm) in striatum of WT and R6/2 mice treated with metformin or vehicle; n = 3. (G) Quantification of number of nodes in individual microglia in striatum of WT and R6/2 mice treated with metformin or vehicle. (H) Quantification of number of endings in individual microglia in the striatum of WT and R6/2 mice treated with metformin or vehicle (10–14 microglial cells per animal, n = 3 animals per group). 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.

Copyright © 2026 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts