OSCR

O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology.

Overview

Authors: Dong Yeol Kim1, Sang-Min Kim1, Chanhaeng Lee1, Inn-Oc Han1,2
ORCID iDs: Inn-Oc Han
  1. Department of Physiology and Biophysics, College of Medicine, Inha University, Incheon, Korea
  2. Department of Biomedical Science, Program in Biomedical Science and Engineering, Inha University, Incheon, Korea
Institutions: Inha University (South Korea)
Journal: Cell death & disease, volume 17, issue 1, article 638
Dates: received 1 September 2025; accepted 7 May 2026; published online 21 May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41419-026-08862-3 · PMID 42161925 · PMCID PMC13365447 · OpenAlex W7161775434
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: human (organism), mouse (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics
Keywords: Alzheimer's disease, Chronic inflammation, Neurodegeneration
MeSH: Alzheimer Disease*, Inflammation*, Microglia*, Acetylglucosamine, Animals, Glucosamine, Hippocampus, Humans, Lipopolysaccharides, Male, Mice, Mice, Inbred C57BL, NF-kappa B, Signal Transduction (* major topic)
Topic: Glycosylation and Glycoproteins Research (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: National Research Foundation of Korea (RS-2024-00346770)
Citations: cited by 1 paper (Europe PMC); 38 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

Code availability

No custom computer code was used in this study.

Reproduced under the paper's license (CC BY), from the paper cited above.

Tracing map

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Data

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Data availability

The data and materials used in this research are available upon request from the corresponding author.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 4 authors, 3 keywords, 14 MeSH terms, 1 funder, 38 references.

Cite

This paper

Kim, D. Y., Kim, S.-M., Lee, C., & Han, I.-O. (2026). O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology. Cell death & disease, 17(1), 638. https://doi.org/10.1038/s41419-026-08862-3

BibTeX

@article{kim2026o,
author = {Kim, Dong Yeol and Kim, Sang-Min and Lee, Chanhaeng and Han, Inn-Oc},
title = {{O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology}},
journal = {Cell death \& disease},
year = {2026},
month = may,
volume = {17},
number = {1},
pages = {638},
publisher = {Nature Publishing Group},
issn = {2041-4889},
doi = {10.1038/s41419-026-08862-3},
url = {https://doi.org/10.1038/s41419-026-08862-3},
pmid = {42161925},
pmcid = {PMC13365447}
}

RIS

TY - JOUR
AU - Kim, Dong Yeol
AU - Kim, Sang-Min
AU - Lee, Chanhaeng
AU - Han, Inn-Oc
TI - O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology
T2 - Cell death & disease
J2 - Cell Death Dis
PY - 2026
DA - 2026/05/21
VL - 17
IS - 1
SP - 638
SN - 2041-4889
PB - Nature Publishing Group
DO - 10.1038/s41419-026-08862-3
UR - https://doi.org/10.1038/s41419-026-08862-3
LA - en
ER -

CSL-JSON

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