Sialylation enhances the secretion of neurotoxic amyloid-β peptides

Alzheimer's disease (AD) is characterized by amyloid-beta peptide (A beta) deposition in the brain. A beta is produced by sequential cleavage of amyloid precursor protein (APP) by beta-secretase (BACE1: beta-site APP-cleaving enzyme 1) and gamma-secretase. Previously, we demonstrated that BACE1 also cleaves beta-galactoside alpha 2,6-sialyltransferase (ST6Gal-I) and down-regulates its transferase activity. Here, we report that overexpression of ST6Gal-I in Neuro2a cells enhanced alpha 2,6-sialylation of endogenous APP and increased the extracellular levels of its metabolites A beta by two-fold, soluble APP beta (sAPP beta) by three-fold and sAPP alpha by 2.5-fold). Sialylation-deficient mutant (Lec-2) cells secreted half as much A beta 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 alpha 2,6-sialylated APP appeared to be correlated with the sAPP beta level. These results suggest that sialylation of APP promotes its metabolic turnover and could affect the pathology of AD.