O-GlcNAcylation Promotes Non-Amyloidogenic Processing of Amyloid-beta Protein Precursor via Inhibition of Endocytosis from the Plasma Membrane
- Authors
- Chun, YS[Chun, Yoon Sun]; Park, Y[Park, Yurim]; Oh, HG[Oh, Hyun Geun]; Kim, TW[Kim, Tae-Wan]; Yang, HO[Yang, Hyun Ok]; Park, MK[Park, Myoung Kyu]; Chung, S[Chung, Sungkwon]
- Issue Date
- 2015
- Publisher
- IOS PRESS
- Keywords
- Alzheimer' s disease; amyloid-beta protein precursor; endocytosis; O-GlcNAcylation
- Citation
- JOURNAL OF ALZHEIMERS DISEASE, v.44, no.1, pp.261 - 275
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF ALZHEIMERS DISEASE
- Volume
- 44
- Number
- 1
- Start Page
- 261
- End Page
- 275
- URI
- https://scholarworks.bwise.kr/skku/handle/2021.sw.skku/48509
- DOI
- 10.3233/JAD-140096
- ISSN
- 1387-2877
- Abstract
- Amyloid-beta protein precursor (A beta PP) is transported to the plasma membrane, where it is sequentially cleaved by alpha-secretase and gamma-secretase. This is called non-amyloidogenic pathway since it precludes the production of amyloid-beta (A beta), the main culprit of Alzheimer's disease (AD). Alternatively, onceA beta PP undergoes clathrin-dependent endocytosis, it can be sequentially cleaved by beta-secretase and gamma-secretase at endosomes, producing A alpha(amyloidogenic pathway). beta -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 A beta PP increases the non-amyloidogenic pathway. To investigate the regulatory role for O-GlcNAcylation in A beta PP processing, we first tested the effects of inhibitor for OGN, PUGNAc, on A beta PP metabolism in HeLa cells stably transfected with Swedish mutant form of A beta PP. Increasing O-GlcNAcylated A beta PP level increased beta-secretase product while decreased beta-secretase products. We found that PUGNAc increased the trafficking rate of A beta PP from the trans-Golgi network to the plasma membrane, and selectively decreased the endocytosis rate of A beta PP. These events may contribute to the increased A beta PP level in the plasma membrane by PUGNAc. Inhibiting clathrin-dependent endocytosis prevented the effect of PUGNAc on A beta, suggesting that the effect of PUGNAc was mainly mediated by decreasing A beta PP endocytosis. These results strongly indicate that O-GlcNAcylation promotes the plasma membrane localization of A beta PP, which enhances the non-amyloidogenic processing of A beta PP. Thus, O-GlcNAcylation of A beta PP can be a potential therapeutic strategy for AD.
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Collections - Medicine > Department of Medicine > 1. Journal Articles
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