Hyeri Kim (Korea Basic Science Institute)

Geum-Sook Hwang (Korea Basic Science Institute)

Hyeri Kim (Korea Basic Science Institute)

Jueun Lee (Korea Basic Science Institute)

Geum-Sook Hwang (Korea Basic Science Institute)

Alzheimers disease (AD) is a representative neurodegenerative disease characterized by memory loss and cognitive impairment, with neuroinflammation and metabolic dysregulation recognized as key pathological mechanisms of AD. Glucosamine (GlcN) has been reported to contribute to memory improvement by activating the hexosamine biosynthetic pathway (HBP). In addition, lipid metabolism is important for maintaining neuronal function and regulating inflammation, and neurotransmitter imbalance significantly affects cognitive decline in Alzheimers disease (AD). However, comprehensive studies on the metabolic effects of GlcN in AD models are still limited.

In this study, we analyzed the changes in HBP metabolites, lipid profiles, and neurotransmitters in hippocampal tissues from a lipopolysaccharide (LPS)-induced AD mouse model (LPS, n = 15) and an LPS model treated with GlcN (LPS-G, n = 13). HBP metabolites were analyzed using gas chromatography-mass spectrometry (GC-MS), lipidomics was performed with liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS), and neurotransmitters were quantified using liquid chromatography-triple mass spectrometry (LC-QQQ/MS).

Compared to the LPS group, the GlcN-treated group showed a significant increase in hippocampal levels of UDP-GlcNAc, a final product of the hexosamine biosynthetic pathway (HBP), suggesting that HBP was activated by GlcN treatment. In contrast, the concentration of the neurotransmitter tryptophan was reduced, potentially due to its conjugation with glucosamine. This tryptophan–glucosamine complex has been shown to inhibit tau protein aggregation, indicating its potential as a therapeutic candidate by modulating tau pathology in Alzheimers disease. In addition, partial least squares discriminant analysis (PLS-DA) of lipid metabolites revealed clear separation between the LPS and LPS-G groups in both positive and negative ion modes. Heatmap analysis of log2 fold changes showed increased levels of phosphatidylethanolamine (PE) and ether-linked PE (PE-O), along with decreased phosphatidylcholine (PC) in the GlcN-treated group.

These results indicate that GlcN modulates multiple metabolic pathways, including HBP activity, lipid remodeling, and neurotransmitter balance, thereby exerting neuroprotective effects in AD. Furthermore, mass spectrometry-based multi-omics approaches offer valuable insights for evaluating therapeutic strategies in neurodegenerative diseases.