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.