Metabolic reprogramming is critical to microglial activation in Huntington's disease
Abhishek Jauhari1, Adam C Monek1, Olena S Abakumova1
1Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.
Insights
Metformin reduces neuroinflammation in Huntington's disease (HD) by inhibiting mitochondrial DNA release and reprogramming microglial metabolism. This drug shifts microglia to a protective state, offering potential therapeutic benefits for HD patients.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder linked to expanded CAG repeats in the Huntingtin gene.
- Neuroinflammation, characterized by microglial activation and pro-inflammatory cytokines, is a hallmark of HD brains.
- The precise mechanisms governing neuroinflammation and microglial responses in HD remain unclear.
Purpose of the Study:
- To investigate the neuroprotective effects of metformin in a mouse model of Huntington's disease.
- To elucidate the mechanisms by which metformin modulates neuroinflammation and microglial activation in HD.
Main Methods:
- Utilized a transgenic mouse model of Huntington's disease.
- Administered metformin and assessed neuroinflammation markers, microglial activation states, and immunometabolism.
- Analyzed mitochondrial dynamics and cellular metabolism in brain tissue and primary microglia.
Main Results:
- Metformin significantly inhibited mitochondrial DNA release and subsequent neuroinflammation in the HD mouse brain.
- Metformin reduced pro-inflammatory cytokines and pathological microglial clustering, promoting a homeostatic microglial phenotype.
- The drug improved aberrant immunometabolism in HD microglia and reprogrammed deregulated cellular metabolism.
Conclusions:
- Metformin exerts neuroprotective effects in Huntington's disease by controlling microglial activation and neuroinflammation.
- The drug's mechanism involves regulating mitochondrial fission, restoring metabolic balance in microglia, and reducing inflammatory responses.
- Metformin demonstrates potential as a therapeutic agent for mitigating neuroinflammation 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.
