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

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-β 42 (Aβ 42 ) 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 Aβ 42 production, while alleviated Aβ 42 -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.