title: O-GlcNAcylation promotes non-amyloidogenic processing of amyloid-β protein precursor via inhibition of endocytosis from the plasma membrane.
abstract: Amyloid-β protein precursor (AβPP) is transported to the plasma membrane, where it is sequentially cleaved by α-secretase and γ-secretase. This is called non-amyloidogenic pathway since it precludes the production of amyloid-β (Aβ), the main culprit of Alzheimer's disease (AD). Alternatively, once AβPP undergoes clathrin-dependent endocytosis, it can be sequentially cleaved by β-secretase and γ-secretase at endosomes, producing Aβ (amyloidogenic pathway). β-N-acetylglucosamine (GlcNAc) can be attached to serine/threonine residues of the target proteins. This novel type of O-linked glycosylation is called O-GlcNAcylation mediated by O-GlcNAc transferase (OGT). The removal of GlcNAc is mediated by O-GlcNAcase (OGN). Recently, it is shown that O-GlcNAcylation of AβPP increases the non-amyloidogenic pathway. To investigate the regulatory role for O-GlcNAcylation in AβPP processing, we first tested the effects of inhibitor for OGN, PUGNAc, on AβPP metabolism in HeLa cells stably transfected with Swedish mutant form of AβPP. Increasing O-GlcNAcylated AβPP level increased α-secretase product while decreased β-secretase products. We found that PUGNAc increased the trafficking rate of AβPP from the trans-Golgi network to the plasma membrane, and selectively decreased the endocytosis rate of AβPP. These events may contribute to the increased AβPP level in the plasma membrane by PUGNAc. Inhibiting clathrin-dependent endocytosis prevented the effect of PUGNAc on Aβ, suggesting that the effect of PUGNAc was mainly mediated by decreasing AβPP endocytosis. These results strongly indicate that O-GlcNAcylation promotes the plasma membrane localization of AβPP, which enhances the non-amyloidogenic processing of AβPP. Thus, O-GlcNAcylation of AβPP can be a potential therapeutic strategy for AD.
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Chun
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
authors.forename: Yurim
authors.initials: Y
authors.lastname: Park
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
authors.forename: Hyun Geun
authors.initials: HG
authors.lastname: Oh
authors.affiliation: Department of Pathology and Cell Biology, and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
authors.forename: Tae-Wan
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Natural Products Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute, Gangneung, Gangwon-do, South Korea.
authors.forename: Hyun Ok
authors.initials: HO
authors.lastname: Yang
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
authors.forename: Myoung Kyu
authors.initials: MK
authors.lastname: Park
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
authors.forename: Sungkwon
authors.initials: S
authors.lastname: Chung
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002966:Clathrin / Q000378:metabolism; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D048448:Phenylcarbamates / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002966:Clathrin; D010091:Oximes; D048448:Phenylcarbamates; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D053829:Amyloid Precursor Protein Secretases; D000117:Acetylglucosamine
keywords: Alzheimer's disease; O-GlcNAcylation; amyloid-β protein precursor; endocytosis