title: O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-β precursor protein (APP).
abstract: The amyloid-β precursor protein (APP) was shown to be O-GlcNAcylated 15 years ago, but the effect of this modification on APP processing and formation of the Alzheimer's disease associated amyloid-β (Aβ) peptide has so far not been investigated. Here, we demonstrate with pharmacological tools or siRNA that O-GlcNAcase and O-GlcNAc transferase regulate the level of O-GlcNAcylated APP. We also show that O-GlcNAcylation increases non-amyloidogenic α-secretase processing, resulting in increased levels of the neuroprotective sAPPα fragment and decreased Aβ secretion. Our results implicate O-GlcNAcylation as a potential therapeutic target for Alzheimer's disease.
authors.affiliation: Department of Neurochemistry, Stockholm University, SE-10691 Stockholm, Sweden.
authors.forename: Kristin T
authors.initials: KT
authors.lastname: Jacobsen
authors.forename: Kerstin
authors.initials: K
authors.lastname: Iverfeldt
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000215:Acylation / Q000187:drug effects / Q000235:genetics; D000544:Alzheimer Disease / Q000201:enzymology* / Q000628:therapy; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D010091:Oximes / Q000494:pharmacology; D048448:Phenylcarbamates / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D010091:Oximes; D048448:Phenylcarbamates; D034741:RNA, Small Interfering; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; D017351:N-Acetylglucosaminyltransferases; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine