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

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journal contribution
posted on 2021-03-08, 05:15 authored by J Park, HJ Ha, ES Chung, SH Baek, Y Cho, HK Kim, J Han, JH Sul, J Lee, E Kim, J Kim, YR Yang, M Park, SH Kim, Thiruma ArumugamThiruma Arumugam, H Jang, SW Seo, PG Suh, DG Jo
© 2021 American Association for the Advancement of Science. All rights reserved. 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.


This study was supported by the National Research Foundation of Korea (NRF-2019R1A2C3011422, NRF-2019R1A5A2027340, NRF-2018M3C7A1021851, and NRF-2017M3C7A1048268) and a grant from the Korea Polar Research Institute (PE20010).


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