Analytica chimica acta · 2026
A robust HPLC-HILIC enrichment system for O-glycoproteomics profiling of plasma and cerebrospinal fluid across Alzheimer's disease progression.
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Deng Zhenpeng, Wang Yan, Liu Lei, Guo Xin, Zhu Haiyang, Dong Mingming, Ge Yusong, Yu Yongliang, Ye Mingliang
Аннотация
BACKGROUND: Alzheimer's disease (AD) pathogenesis involves widespread molecular alterations in both brain tissue and peripheral biofluids, yet the role of protein O-linked glycosylation in disease progression remains poorly characterized due to technical limitations in comprehensive O-glycoproteome profiling.
RESULTS: To address this gap, we developed a robust high-performance liquid chromatography-hydrophilic interaction chromatography (HPLC-HILIC) system optimized for efficient enrichment of intact O-glycopeptides from protein digests of complex biological matrices. This system was applied to characterize the O-glycoproteomes of plasma samples across different stages of AD progression, as well as those of cerebrospinal fluid (CSF) from AD patients. Notably, in plasma, it was found that fucosylated glycopeptides were down-regulated and sialylated glycopeptides were up-regulated as the disease progressed. In contrast, CSF samples exhibited an increased number of O-glycopeptides, accompanied by higher levels of sialylation. Furthermore, analysis of O-glycosylation patterns in AD CSF and plasma following blood-brain barrier disruption revealed increased O-glycosylation of ITIH4 (Q14624) and SERPINA5 (P05154) in plasma, and enhanced sialylated O-glycosylation of APOE (P02649) in CSF. These observations suggest that sialylated O- glycosylation may play a crucial role in the pathology of AD.
SIGNIFICANCE: Collectively, a robust O-glycoproteomic workflow was presented to investigate O-glycosylation patterns between CSF and plasma in AD. The results provide valuable insights into the involvement of O-glycosylation in AD progression and highlight the potential of this analytical platform for studying O-glycosylation dynamics in AD and other neurodegenerative disorders.
RESULTS: To address this gap, we developed a robust high-performance liquid chromatography-hydrophilic interaction chromatography (HPLC-HILIC) system optimized for efficient enrichment of intact O-glycopeptides from protein digests of complex biological matrices. This system was applied to characterize the O-glycoproteomes of plasma samples across different stages of AD progression, as well as those of cerebrospinal fluid (CSF) from AD patients. Notably, in plasma, it was found that fucosylated glycopeptides were down-regulated and sialylated glycopeptides were up-regulated as the disease progressed. In contrast, CSF samples exhibited an increased number of O-glycopeptides, accompanied by higher levels of sialylation. Furthermore, analysis of O-glycosylation patterns in AD CSF and plasma following blood-brain barrier disruption revealed increased O-glycosylation of ITIH4 (Q14624) and SERPINA5 (P05154) in plasma, and enhanced sialylated O-glycosylation of APOE (P02649) in CSF. These observations suggest that sialylated O- glycosylation may play a crucial role in the pathology of AD.
SIGNIFICANCE: Collectively, a robust O-glycoproteomic workflow was presented to investigate O-glycosylation patterns between CSF and plasma in AD. The results provide valuable insights into the involvement of O-glycosylation in AD progression and highlight the potential of this analytical platform for studying O-glycosylation dynamics in AD and other neurodegenerative disorders.