Dynamic Change of Intracellular Metabolism of Microglia Evaluated by Transcriptomics in an Alzheimer's Mouse Model
Hongyan Qiu1, Ruoqi Zhao1, Guoqiang Fei1,2
1Department of Neurology, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China.
Background:
Microglia play diverse roles in Alzheimer's disease (AD). Intracellular metabolism has been indicated an important factor in modulating the function of microglia. However, it is not clear whether the intracellular metabolism of microglia changes dynamically in different stages of AD.
Objective:
To determine whether microglia intracellular metabolism changes dynamically in different stages of AD.
Methods:
Microglia were extracted from APPSwe/PS1dE9 (APP/PS1) mice and wild-type littermates at 2, 4, and 8 months old by fluorescence-activated cell sorting and used for RNA-sequencing analysis and quantitative PCR. Morphologies of amyloid plaques and microglia were detected by immunofluorescence staining.
Results:
Compared with control littermates, the microglia of APP/PS1 mice exhibited significant transcriptional changes at 2-month-old before microglia morphological alterations and the plaque formation. The changes continued drastically following age with defined morphological shift of microglia and amyloid plaque enhancement in brains. Further analysis of those genotype and age dependent transcriptomic changes revealed that differentially expressed genes were enriched in pathways related to energy metabolism. Compared with wild-type mice, there were changes of some vital genes related to glucose metabolism and lipid metabolism pathways in APP/PS1 mice at different ages. Glucose metabolism may play a major role in early activation of microglia, and lipid metabolism may be more important in later activation period.
Conclusion:
Our results showed that microglia actively participate in the pathological progress of AD. The intracellular metabolism of microglia changed significantly in different stages of AD, even preceding amyloid-β deposition.
Insights
Microglia metabolism shifts dynamically during Alzheimer's disease (AD) progression, even before amyloid-beta plaque formation. These changes in glucose and lipid metabolism are crucial for understanding microglial roles in AD pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Metabolic Research
Background:
- Microglia, the immune cells of the brain, have multifaceted roles in Alzheimer's disease (AD).
- Intracellular metabolism significantly influences microglial function.
- Dynamic changes in microglial metabolism across AD stages remain unclear.
Purpose of the Study:
- To investigate dynamic alterations in microglia intracellular metabolism during different stages of AD.
- To correlate metabolic changes with AD pathology and microglial activation.
Main Methods:
- Microglia isolation from APPSwe/PS1dE9 (APP/PS1) and wild-type mice at 2, 4, and 8 months using fluorescence-activated cell sorting.
- RNA-sequencing and quantitative PCR for transcriptional analysis.
- Immunofluorescence staining for assessing amyloid plaque and microglia morphology.
Main Results:
- Significant transcriptional changes in APP/PS1 microglia observed at 2 months, preceding morphological changes and plaque deposition.
- Transcriptomic alterations intensified with age, correlating with microglial morphological shifts and increased amyloid plaques.
- Differentially expressed genes enriched in energy metabolism pathways, with notable changes in glucose and lipid metabolism genes.
Conclusions:
- Microglia actively contribute to Alzheimer's disease progression.
- Microglial intracellular metabolism undergoes significant changes throughout AD stages, starting even before amyloid-beta deposition.
- Glucose metabolism appears critical in early microglial activation, while lipid metabolism gains importance in later stages.
