Sialylation enhances the secretion of neurotoxic amyloid-beta peptides.
Alzheimer's disease (AD) is characterized by amyloid-beta peptide (Abeta) deposition in the brain. Abeta 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 alpha2,6-sialyltransferase (ST6Gal-I) and down-regulates its transferase activity. Here, we report that overexpression of ST6Gal-I in Neuro2a cells enhanced alpha2,6-sialylation of endogenous APP and increased the extracellular levels of its metabolites [Abeta by two-fold, soluble APPbeta (sAPPbeta) by three-fold and sAPPalpha by 2.5-fold). Sialylation-deficient mutant (Lec-2) cells secreted half as much Abeta 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 alpha2,6-sialylated APP appeared to be correlated with the sAPPbeta level. These results suggest that sialylation of APP promotes its metabolic turnover and could affect the pathology of AD.
Nakagawa
Kazuhiro
K
Glycochain Functions Laboratory, Suprabiomolecular System Group, Frontier Research System, RIKEN, Wako-shi, Saitama, Japan.
Kitazume
Shinobu
S
Oka
Ritsuko
R
Maruyama
Kei
K
Saido
Takaomi C
TC
Sato
Yuji
Y
Endo
Tamao
T
Hashimoto
Yasuhiro
Y
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012799:Sialyltransferases / Q000378:metabolism; D014162:Transfection; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011994:Recombinant Proteins; D012799:Sialyltransferases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; C509281:Bace1 protein, rat; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase