O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer's disease by inhibiting necroptosis

Cited 61 time in scopus
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Title
O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer's disease by inhibiting necroptosis
Author(s)
J Park; H J Ha; E S Chung; S H Baek; Y Cho; H K Kim; J Han; J H Sul; J Lee; E Kim; J Kim; Yong Ryoul Yang; M Park; S H Kim; T V Arumugam; H Jang; S W Seo; P G Suh; D G Jo
Bibliographic Citation
Science Advances, vol. 7, no. 3, pp. eabd3207-eabd3207
Publication Year
2021
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.
ISSN
2375-2548
Publisher
Amer Assoc Advancement Science
DOI
http://dx.doi.org/10.1126/sciadv.abd3207
Type
Article
Appears in Collections:
Aging Convergence Research Center > 1. Journal Articles
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