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.
Copyright © 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylglucosamine / analogs & derivatives
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Acetylglucosamine / genetics
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Acetylglucosamine / metabolism*
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Acetylglucosamine / pharmacology
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Acylation / drug effects
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Acylation / genetics
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Alzheimer Disease / enzymology*
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Alzheimer Disease / therapy
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Amyloid beta-Protein Precursor / metabolism*
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Cell Line, Tumor
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Gene Knockdown Techniques
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Humans
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N-Acetylglucosaminyltransferases / genetics
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N-Acetylglucosaminyltransferases / metabolism*
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Oximes / pharmacology
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Phenylcarbamates / pharmacology
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RNA, Small Interfering / genetics
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beta-N-Acetylhexosaminidases / antagonists & inhibitors
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beta-N-Acetylhexosaminidases / genetics
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beta-N-Acetylhexosaminidases / metabolism*
Substances
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APP protein, human
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Amyloid beta-Protein Precursor
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Oximes
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Phenylcarbamates
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RNA, Small Interfering
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N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime
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N-Acetylglucosaminyltransferases
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hexosaminidase C
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beta-N-Acetylhexosaminidases
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Acetylglucosamine