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O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer's disease by inhibiting necroptosisopen access
- Authors
- Park, J.[Park, J.]; Ha, H.-J.[Ha, H.-J.]; Chung, E.S.[Chung, E.S.]; Baek, S.H.[Baek, S.H.]; Cho, Y.[Cho, Y.]; Kim, H.K.[Kim, H.K.]; Han, J.[Han, J.]; Sul, J.H.[Sul, J.H.]; Lee, J.[Lee, J.]; Kim, E.[Kim, E.]; Kim, J.[Kim, J.]; Yang, Y.R.[Yang, Y.R.]; Park, M.[Park, M.]; Kim, S.H.[Kim, S.H.]; Arumugam, T.V.[Arumugam, T.V.]; Jang, H.[Jang, H.]; Seo, S.W.[Seo, S.W.]; Suh, P.-G.[Suh, P.-G.]; Jo, D.-G.[Jo, D.-G.]
- Issue Date
- Jan-2021
- Publisher
- American Association for the Advancement of Science
- Citation
- Science Advances, v.7, no.3
- Indexed
- SCIE
SCOPUS
- Journal Title
- Science Advances
- Volume
- 7
- Number
- 3
- ISSN
- 2375-2548
- Abstract
- O-GlcNAcylation (O-linked β-N-acetylglucosaminylation) is notably decreased in Alzheimer's disease (AD) brain. Necroptosis is activated in AD brain and is positively correlated with neuroinflammation and tau pathology. However, the links among altered O-GlcNAcylation, β-amyloid (Aβ) accumulation, and necroptosis are unclear. Here, we found that O-GlcNAcylation plays a protective role in AD by inhibiting necroptosis. Necroptosis was increased in AD patients and AD mouse model compared with controls; however, decreased necroptosis due to O-GlcNAcylation of RIPK3 (receptor-interacting serine/threonine protein kinase 3) was observed in 5xFAD mice with insufficient O-linked β-N-acetylglucosaminase. O-GlcNAcylation of RIPK3 suppresses phosphorylation of RIPK3 and its interaction with RIPK1. Moreover, increased O-GlcNAcylation ameliorated AD pathology, including Aβ burden, neuronal loss, neuroinflammation, and damaged mitochondria and recovered the M2 phenotype and phagocytic activity of microglia. Thus, our data establish the influence of O-GlcNAcylation on Aβ accumulation and neurodegeneration, suggesting O-GlcNAcylation-based treatments as potential interventions for AD. © 2021 American Association for the Advancement of Science. All rights reserved.
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