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

ABSTRACT: O-GlcNAcylation (O-linked ?-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, ?-amyloid (A?) 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 ?-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 A? accumulation and neurodegeneration, suggesting O-GlcNAcylation-based treatments as potential interventions for AD.

SUBMITTER: Park J

PROVIDER: S-EPMC7806231 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Park Jinsu J Ha Hee-Jin HJ Chung Eun Seon ES Baek Seung Hyun SH Cho Yoonsuk Y Kim Hark Kyun HK Han Jihoon J Sul Jae Hoon JH Lee Jeongmi J Kim Eunae E Kim Junsik J Yang Yong Ryoul YR Park Mikyoung M Kim Sung Hyun SH Arumugam Thiruma V TV Jang Hyemin H Seo Sang Won SW Suh Pann-Ghill PG Jo Dong-Gyu DG

Science advances 20210113 3

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 ...[more]

PMID: 33523877

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Project description:BackgroundAccumulating evidence indicated that necroptosis plays an essential role in the pathogenesis of inflammatory bowel disease (IBD). The O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) of necroptotic signal molecule receptor-interacting serine-threonine kinase 3 (RIPK3) was reported to exert a protective effect in gut inflammation. Our recent study suggested traditional Chinese herbal formula Wu-Mei-Wan (WMW) as an effective prescription in mouse colitis. However, the potential mechanisms are not fully understood. Considering the crucial role of necroptosis in the pathogenesis of IBD, therefore, this study was designed to explain whether the anti-colitis effect of WMW is mediated by modulating necroptosis and its related mechanisms.MethodsThe protective effects of WMW on colitis have been determined by detecting colitis mice body weight, disease activity index (DAI), survival rate and colon length. Colonic inflammation was examined by inflammatory cells infiltration and local cytokines levels. After then, we measured the levels of necroptosis and O-GlcNAcylation. C O-immunoprecipitation experiments were used to address whether elevated O-GlcNAcylation can inhibit necroptotic signal transduction in the treatment of WMW. Finally, the key enzymes in O-GlcNAcylation: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) were examined and molecular docking analysis was used to determine effective natural compounds in the regulation on OGT and OGA activities.ResultsOur results showed that WMW significantly improved mice body weight, survival rate and colon length, decreased DAI in TNBS-induced colitis. WMW obviously alleviated colonic inflammatory responses with reduced macrophages, neutrophils infiltration and local IL-1β, IL-6, TNF-α and IFN-γ levels. It was found that WMW increased colonic O-GlcNAcylation level and inhibited the activation of RIPK1, RIPK3 and MLKL. Then, further experiments revealed that WMW enhanced OGT activity and suppressed OGA activity, thereby increasing RIPK3 O-GlcNAcylation and inhibiting the binding of RIPK3 and MLKL, which led to the inhibition of necroptosis. Additionally, docking analysis demonstrated that hesperidin, coptisine and ginsenoside Rb1 may exert a major role in the regulation on OGT and OGA activities by WMW.ConclusionOur work demonstrated that WMW can alleviate TNBS-induced colitis in mice by inhibiting necroptosis through increasing RIPK3 O-GlcNAcylation.

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

Publications

<i>O</i>-GlcNAcylation ameliorates the pathological manifestations of Alzheimer's disease by inhibiting necroptosis.

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