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Updated: May 5, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Glutamine metabolism modulates microglial NLRP3 inflammasome activity through mitophagy in Alzheimer's disease
Zhixin Zhang1,2, Miao Li1, Xiang Li1
1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
Abstract:
The NLR family pyrin domain containing 3 (NLRP3) inflammasome in microglia is intimately linked to the pathogenesis of Alzheimer's disease (AD). Although NLRP3 inflammasome activity is regulated by cellular metabolism, the underlying mechanism remains elusive. Here, we found that under the pathological conditions of AD, the activation of NLRP3 inflammasome in microglia is accompanied by increased glutamine metabolism. Suppression of glutaminase, the rate limiting enzyme in glutamine metabolism, attenuated the NLRP3 inflammasome activation both in the microglia of AD mice and cultured inflammatory microglia. Mechanistically, inhibiting glutaminase blocked the anaplerotic flux of glutamine to the tricarboxylic acid cycle and amino acid synthesis, down-regulated mTORC1 signaling by phosphorylating AMPK, which stimulated mitophagy and limited the accumulation of intracellular reactive oxygen species, ultimately prevented the activation of NLRP3 inflammasomes in activated microglia during AD. Taken together, our findings suggest that glutamine metabolism regulates the activation of NLRP3 inflammasome through mitophagy in microglia, thus providing a potential therapeutic target for AD treatment.
Insights
In Alzheimer
Area of Science:
- Neuroscience
- Immunology
- Cellular Metabolism
Background:
- The NLRP3 inflammasome in microglia plays a key role in Alzheimer's disease (AD) pathogenesis.
- Cellular metabolism influences NLRP3 inflammasome activity, but the precise mechanisms are unclear.
Purpose of the Study:
- To investigate the role of glutamine metabolism in regulating microglial NLRP3 inflammasome activation in Alzheimer's disease.
Main Methods:
- Studied microglia from AD mice and cultured inflammatory microglia.
- Utilized glutaminase inhibition to assess its impact on NLRP3 inflammasome activation.
- Analyzed metabolic pathways including the tricarboxylic acid cycle, mTORC1 signaling, and mitophagy.
Main Results:
- Increased glutamine metabolism correlated with NLRP3 inflammasome activation in AD microglia.
- Suppression of glutaminase attenuated NLRP3 inflammasome activation.
- Inhibiting glutaminase reduced reactive oxygen species accumulation via mitophagy and mTORC1 signaling.
- This ultimately prevented NLRP3 inflammasome activation in activated microglia.
Conclusions:
- Glutamine metabolism regulates microglial NLRP3 inflammasome activation through mitophagy.
- Targeting glutamine metabolism presents a potential therapeutic strategy for Alzheimer's disease.
