Targeting ST6Gal-I shows promise in reducing Alzheimer’s disease pathology

A recent study published in Engineering has provided novel insights into the involvement of α2,6-sialylation in Alzheimer's disease (AD), revealing that the ablation of α2,6-sialyltransferase-I (ST6Gal-I), an enzyme responsible for α2,6-sialylation, can downregulate BACE1 expression and suppress the production of amyloid-β₄₂ (Aβ₄₂) plaques, which are hallmarks of AD.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by the gradual loss of memory and cognitive functions. The amyloidogenic hypothesis suggests that the aggregation of Aβ plaques is a key pathological driver of AD. Ab peptides are generated by the sequential processing of amyloid precursor protein (APP) by b-site amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase. BACE1 plays a crucial role in the biosynthesis of Ab peptides during AD pathogenesis. Glycosylation, a post-translational modification involving the addition of oligosaccharides to proteins, has been implicated in the development and progression of AD. However, the specific role of α2,6-sialylation, catalyzed by ST6Gal-I, in AD has remained unclear.

In this study, researchers from multiple institutions, including the Cancer Hospital of Shantou University Medical College and the Institute for Genome Engineered Animal Models of Human Diseases at Dalian Medical University, investigated the expression of ST6Gal-I and α2,6-sialylation levels in cerebrospinal fluid (CSF) and sera of AD patients, as well as in AD model mice. They found that both ST6Gal-I expression and α2,6-sialylation levels were significantly upregulated in these samples. The study also demonstrated that deletion of ST6Gal-I in rats reduced BACE1 levels and alleviated learning and memory impairments induced by scopolamine, a pharmacological tool used to study AD-like cognitive deficits.

The researchers used CRISPR/Cas9 gene-editing technology to generate ST6Gal-I knockout (ST6Gal-I^–/–) rats. These rats exhibited reduced α2,6-sialylation levels and decreased BACE1 expression in the brain. Behavioral experiments, including the Morris water maze test, nest-building test, and novel object recognition test, showed that ST6Gal-I^–/– rats had attenuated cognitive impairments compared to their wild-type counterparts after scopolamine treatment. In addition, the study revealed that ST6Gal-I knockdown in Neuro-2a neuroblastoma cells (ST6Gal-I-KD-N2a) reduced BACE1 expression by promoting its ubiquitination, leading to decreased Aβ₄₂ production and reduced apoptosis.

The findings of this study highlight the significant role of α2,6-sialylation in the development and progression of AD, suggesting that ST6Gal-I could be a potential therapeutic target for the diagnosis and treatment of AD. By elucidating the mechanism through which α2,6-sialylation affects BACE1 expression and Aβ₄₂ production, this research opens new avenues for exploring glycomedicine approaches to combat AD. Future studies may focus on further investigating the molecular pathways involved in the regulation of α2,6-sialylation and its impact on AD pathology, as well as developing therapeutic strategies targeting ST6Gal-I to mitigate the cognitive deficits associated with AD.

All clinical experiments were approved by the Ethics Committee of the First Affiliated Hospital of Shantou University Medical College (No. B-2023-017).