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Updated: May 22, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology
Dong Yeol Kim1, Sang-Min Kim1, Chanhaeng Lee1
1Department of Physiology and Biophysics, College of Medicine, Inha University, Incheon, Korea.
Abstract:
Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial polarization, elevated NF-κB signaling, and NLRP3 inflammasome activation. In an LPS-induced neuroinflammation model exhibiting AD-relevant inflammatory and cognitive features, as well as in in vitro microglial cultures, LPS exposure led to a pronounced decrease in O-GlcNAcylation, particularly within Iba1-positive microglia. Systemic or in vitro treatment with glucosamine (GlcN) effectively restored O-GlcNAc levels, suppressed M1-associated inflammatory pathways, and promoted an anti-inflammatory M2 phenotype. Mechanistically, GlcN enhanced O-GlcNAcylation of NF-κB subunits p65 and c-Rel, limiting their nuclear translocation and downstream pro-inflammatory gene expression. Notably, GlcN treatment ameliorated LPS-induced memory deficits and neuronal loss in mice. Collectively, these findings suggest that O-GlcNAcylation acts as a modulatory regulator of microglial activation and neuroinflammation in AD, and that enhancing O-GlcNAcylation may represent a potential therapeutic strategy to preserve immune homeostasis and neuronal integrity.
Insights
Enhancing O-GlcNAcylation, a cellular process, can reduce neuroinflammation in Alzheimer
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Chronic neuroinflammation driven by microglia is central to Alzheimer's disease (AD) progression.
- O-GlcNAcylation, a nutrient-sensitive modification, regulates cellular stress and inflammation, but its role in AD-related microglial activation is unknown.
Purpose of the Study:
- To investigate the role of O-GlcNAcylation in microglial activation and neuroinflammation in Alzheimer's disease.
- To explore the therapeutic potential of enhancing O-GlcNAcylation in AD models.
Main Methods:
- Analysis of hippocampal tissue from AD patients.
- Utilized an LPS-induced neuroinflammation mouse model and in vitro microglial cultures.
- Administered glucosamine (GlcN) to modulate O-GlcNAcylation levels.
- Assessed microglial polarization, NF-κB signaling, NLRP3 inflammasome activation, and cognitive function.
Main Results:
- AD patient brains showed reduced O-GlcNAcylation, increased M1 microglial polarization, and elevated NF-κB and NLRP3 inflammasome activity.
- LPS exposure decreased O-GlcNAcylation in microglia, while GlcN treatment restored levels, suppressed M1 markers, and promoted M2 phenotype.
- GlcN treatment inhibited NF-κB nuclear translocation, reduced pro-inflammatory gene expression, and ameliorated LPS-induced memory deficits and neuronal loss.
Conclusions:
- O-GlcNAcylation modulates microglial activation and neuroinflammation in Alzheimer's disease.
- Enhancing O-GlcNAcylation via glucosamine may be a viable therapeutic strategy for AD.
- Targeting O-GlcNAcylation could help preserve immune homeostasis and neuronal integrity in AD.
