PT  - JOURNAL ARTICLE
AU  - Park, Jinsu
AU  - Ha, Hee-Jin
AU  - Chung, Eun Seon
AU  - Baek, Seung Hyun
AU  - Cho, Yoonsuk
AU  - Kim, Hark Kyun
AU  - Han, Jihoon
AU  - Sul, Jae Hoon
AU  - Lee, Jeongmi
AU  - Kim, Eunae
AU  - Kim, Junsik
AU  - Yang, Yong Ryoul
AU  - Park, Mikyoung
AU  - Kim, Sung Hyun
AU  - Arumugam, Thiruma V.
AU  - Jang, Hyemin
AU  - Seo, Sang Won
AU  - Suh, Pann-Ghill
AU  - Jo, Dong-Gyu
TI  - <em>O</em>-GlcNAcylation ameliorates the pathological manifestations of Alzheimer’s disease by inhibiting necroptosis
AID  - 10.1126/sciadv.abd3207
DP  - 2021 Jan 01
TA  - Science Advances
PG  - eabd3207
VI  - 7
IP  - 3
4099  - http://advances.sciencemag.org/content/7/3/eabd3207.short
4100  - http://advances.sciencemag.org/content/7/3/eabd3207.full
SO  - Sci Adv2021 Jan 01; 7
AB  - 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.