Sialylation enhances the secretion of neurotoxic amyloid‐β peptides

Alzheimer's disease (AD) is characterized by amyloid‐β peptide (Aβ) deposition in the brain. Aβ is produced by sequential cleavage of amyloid precursor protein (APP) by β‐secretase (BACE1: β‐site APP‐cleaving enzyme 1) and γ‐secretase. Previously, we demonstrated that BACE1 also cleaves β‐galactoside α2,6‐sialyltransferase (ST6Gal‐I) and down‐regulates its transferase activity. Here, we report that overexpression of ST6Gal‐I in Neuro2a cells enhanced α2,6‐sialylation of endogenous APP and increased the extracellular levels of its metabolites [Aβ by two‐fold, soluble APPβ (sAPPβ) by three‐fold and sAPPα by 2.5‐fold). Sialylation‐deficient mutant (Lec‐2) cells secreted half as much Aβ as wild‐type Chinese hamster ovary (CHO) cells. Furthermore, wild‐type CHO cells showed enhanced secretion of the APP metabolites upon ST6Gal‐I overexpression, whereas Lec‐2 cells did not, indicating that the secretion enhancement requires sialylation of cellular protein(s). Secretion of metabolites from a mutant APP (APP‐Asn467,496Ala) that lacked N‐glycosylation sites was not enhanced upon ST6Gal‐I overexpression, suggesting that the N‐glycans on APP itself are required for the enhanced secretion. In the mouse brain, the amount of α2,6‐sialylated APP appeared to be correlated with the sAPPβ level. These results suggest that sialylation of APP promotes its metabolic turnover and could affect the pathology of AD.