O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer’s disease by inhibiting necroptosis
- O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer’s disease by inhibiting necroptosis
- 박미경; Jinsu Park; Hee-Jin Ha; Eun Seon Chung; Seung Hyun Baek; Yoonsuk Cho; Hark Kyun Kim; Jihoon Han; Jae Hoon Sul; Jeongmi Lee; Eunae Kim; Junsik Kim; Yong Ryoul Yang; Sung Hyun Kim; Thiruma V. Arumugam; Hyemin Jang; Sang Won Seo; Pann-Ghill Suh; Dong-Gyu Jo
- O-GlcNAcylation; Alzheimer’s disease; necroptosis
- Issue Date
- Science Advances
- VOL 7, NO 3, eabd3207
- O-GlcNAcylation (O-linked beta-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, beta-amyloid (Abeta) 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 beta-N-acetylglucosaminase. O-GlcNAcylation of RIPK3 suppresses phosphorylation of RIPK3 and its interaction with RIPK1. Moreover, increased O-GlcNAcylation ameliorated AD pathology, including A？ 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 Abeta accumulation and neurodegeneration, suggesting O-GlcNAcylation？based treatments as potential interventions for AD.
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