糖基化修饰与阿尔茨海默病（AD）发生相关。由α2,6-唾液酸转移酶-I（ST6Gal-I）催化的α2,6-唾液酸基化修饰与婴儿大脑及神经系统的发育相关，然而，异常α2,6-唾液酸基化修饰影响AD发生发展的机制尚未报道。本研究中我们发现，AD患者脑脊液和血清中ST6Gal-I的表达及α2,6-唾液酸化水平均显著上调。AD模型小鼠的大脑和血清中α2,6-唾液酸化水平也显著升高。ST6Gal-I基因敲除降低β-位点淀粉样前体蛋白切割酶1（BACE1）水平，从而改善东莨菪碱诱导的大鼠学习记忆能力。BACE1是一种高度唾液酸基化蛋白，在淀粉样蛋白-β₄₂（Aβ₄₂）蓄积过程中发挥关键作用。ST6Gal-I基因沉默促进神经母细胞瘤细胞（Neuro-2a）的BACE1泛素化，并下调其表达。同时，ST6Gal-I基因敲除抑制BACE1对淀粉样前体蛋白（APP）的切割，从而减少Aβ42生成。本研究首次揭示了α2,6-唾液酸基化修饰在AD发生发展中的重要作用，提示ST6Gal-I可作为AD诊断与治疗的新靶点。

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 β-site amyloid precursor protein cleaving enzyme 1 (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 cells (ST6Gal-I-KD-N2a) reduced the expression of 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.