Inhibition of glycan sialylation reduces amyloid-β secretion via suppression of amyloid-β exocytosis.

Among nutrient-sensitive regulatory mechanisms, protein glycosylation is a key post-translational modification that links metabolism to protein function. Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). Because excessive accumulation of Aβ is believed to drive AD progression, approaches that reduce Aβ production and secretion remain of considerable therapeutic interest. Accumulating evidence suggests that protein glycosylation influences the processing and trafficking of amyloid-β precursor protein (APP) and other proteins involved in Aβ metabolism. However, while N-linked protein glycosylation has been shown to affect Aβ production, the specific contribution of protein terminal glycan sialylation remains incompletely understood. In this study, we investigated the effects of inhibiting glycan sialylation on Aβ production using CHO cells stably expressing human APP. Treatment with the sialyltransferase inhibitor P-3Fax-Neu5Ac (P-3Fax) significantly reduced extracellular Aβ levels, while intracellular Aβ levels were increased. Importantly, P-3Fax treatment did not alter β-secretase- or γ-secretase-mediated cleavage of their substrates, indicating that changes in secretase activity do not account for the reduction in extracellular Aβ. In addition, P-3Fax treatment markedly reduced plasma membrane levels of lysosome-associated membrane protein 1 (LAMP1), consistent with impaired lysosomal exocytosis. Taken together, these results indicate that inhibition of sialylation by P-3Fax reduces extracellular Aβ levels independently of secretase activity, potentially through impaired lysosomal exocytotic pathways. Our findings identify glycan sialylation as a key regulatory factor in Aβ trafficking and provide new insight into the cellular mechanisms controlling Aβ homeostasis.