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Published on: February 5, 2018
The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer's disease
Xudong Sha1, Jiayuan Lin1, Kexin Wu1
1Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Abstract:
Microglia are progressively activated by inflammation and exhibit phagocytic dysfunction in the pathogenesis of neurodegenerative diseases. Lipid-droplet-accumulating microglia were identified in the aging mouse and human brain; however, little is known about the formation and role of lipid droplets in microglial neuroinflammation of Alzheimer's disease (AD). Here, we report a striking buildup of lipid droplets accumulation in microglia in the 3xTg mouse brain. Moreover, we observed significant upregulation of PKM2 and sterol regulatory element binding protein 1 (SREBP1) levels, which were predominantly localized in microglia of 3xTg mice. PKM2 dimerization was necessary for SREBP1 activation and lipogenesis of lipid droplet-accumulating microglia. RNA sequencing analysis of microglia isolated from 3xTg mice exhibited transcriptomic changes in lipid metabolism, innate inflammation, and phagocytosis dysfunction; these changes were improved with capsaicin-mediated pharmacological activation of TRPV1 via inhibition of PKM2 dimerization and reduction of SREBP1 activation. Lipid droplet-accumulating microglia exhibited increased mitochondrial injury accompanied by impaired mitophagy, which was abrogated upon of TRPV1 activation. Capsaicin also rescued neuronal loss, tau pathology, and memory impairment in 3xTg mice. Our study suggests that TRPV1-PKM2-SREBP1 axis regulation of microglia lipid metabolism could be a therapeutic approach to alleviate the consequences of AD.
Insights
Lipid droplets in microglia drive neuroinflammation in Alzheimer's disease (AD). Activating TRPV1 with capsaicin reduces lipid buildup, improves microglial function, and alleviates AD symptoms in mice.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the brain's immune cells, become dysfunctional during neuroinflammation in diseases like Alzheimer's disease (AD).
- Lipid droplets accumulate in microglia in aging brains, but their role in AD neuroinflammation is unclear.
- This study investigates lipid droplet formation and its impact on microglial function in an AD mouse model.
Purpose of the Study:
- To investigate the role of lipid droplets in microglia during Alzheimer's disease pathogenesis.
- To identify molecular pathways regulating lipid droplet accumulation in microglia.
- To explore therapeutic strategies targeting microglial lipid metabolism for AD treatment.
Main Methods:
- Analysis of microglia from 3xTg AD mouse brains to identify lipid droplet accumulation.
- Measurement of PKM2 and SREBP1 levels and their localization within microglia.
- RNA sequencing of microglia to assess transcriptomic changes; in vivo treatment with capsaicin targeting TRPV1.
Main Results:
- Significant lipid droplet accumulation observed in microglia of 3xTg mice, associated with increased PKM2 and SREBP1.
- PKM2 dimerization was essential for SREBP1 activation and lipogenesis in lipid-droplet-accumulating microglia.
- Capsaicin treatment via TRPV1 activation reduced lipid metabolism changes, improved mitochondrial function, abrogated mitophagy impairment, and rescued neuronal loss, tau pathology, and memory deficits in 3xTg mice.
Conclusions:
- The TRPV1-PKM2-SREBP1 axis regulates microglial lipid metabolism and neuroinflammation in AD.
- Targeting this axis offers a potential therapeutic strategy for Alzheimer's disease.
- Modulating microglial lipid metabolism can mitigate AD-associated pathology and cognitive decline.
