Ablation of ST6Gal-I Downregulates BACE1 Expression and Suppresses Production of Aβ42 Plaques in Alzheimer’s Disease

Kangkang Yang , Xueying Li , Minchao Lai , Weiwei Zhao , Wanli Song , Shaobin Chen , Wenzhe Li

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Engineering ›› DOI: 10.1016/j.eng.2025.02.016

Ablation of ST6Gal-I Downregulates BACE1 Expression and Suppresses Production of Aβ42 Plaques in Alzheimer’s Disease

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Abstract

Recent studies indicate the involvement of glycosylation in the pathogenesis of Alzheimer’s disease (AD). α2,6-Sialylation, catalyzed by α2,6-sialyltransferase-I (ST6Gal-I), corresponds to the development of the infant brain and nervous system, however the mechanism of aberrant α2,6-sialylation affects multiple physiological and pathological conditions remains unclear. The present study, in vitro and in vivo, showed that expression of ST6Gal-I and α2,6-sialylation levels were up-regulated in cerebrospinal fluid and sera of AD patients. In addition, levels of α2,6-sialylation were also increased in brain and sera of AD model mice. Furthermore, deletion of ST6Gal-I reduced BACE1 levels and alleviated the impairment of learning and memory induced by scopolamine in rats. BACE1, a hyper-sialylated protein, plays a critical role in amyloid-β42 (Aβ42) production. ST6Gal-I knockdown in Neuro-2a neuroblastoma (ST6Gal-I-KD-N2a) cells reduced the expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) via promoting its ubiquitination. Deletion of ST6Gal-I suppressed amyloid precursor protein (APP) cleaved by BACE1, followed by a decrease in Aβ42 production, while alleviated Aβ42-induced apoptosis. This study first reveals a significant role of α2,6-sialylation in development and progression of AD, suggesting that ST6Gal-I is a novel glycan therapeutic target for AD diagnosis and treatment.

Keywords

α2,6-Sialyltransferase-I / Sialylation / β-Site amyloid precursor protein cleaving enzyme 1 / Amyloid-β42 / Alzheimer’s disease

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Kangkang Yang, Xueying Li, Minchao Lai, Weiwei Zhao, Wanli Song, Shaobin Chen, Wenzhe Li. Ablation of ST6Gal-I Downregulates BACE1 Expression and Suppresses Production of Aβ42 Plaques in Alzheimer’s Disease. Engineering DOI:10.1016/j.eng.2025.02.016

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CRediT authorship contribution statement

Kangkang Yang: Writing – original draft, Visualization, Validation, Software, Formal analysis. Xueying Li: Supervision, Software, Methodology, Investigation, Formal analysis, Data curation. Minchao Lai: Writing – original draft, Resources, Project administration, Conceptualization. Weiwei Zhao: Supervision, Software, Data curation, Conceptualization. Wanli Song: Visualization, Software, Resources, Conceptualization. Shaobin Chen: Project administration, Methodology. Wenzhe Li: Writing – review & editing, Project administration, Investigation, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (32171279), the Guangdong Basic and Applied Basic Research Foundation (2024A1515012796), the Scientific Research Initiation Grant from Shantou University Medical College (510858066), and the Provincial Science and Technology Innovation Strategy Special City and County Science and Technology Innovation Support Project (STKJ2023008).

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