O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer's disease by inhibiting necroptosis.
Jin Su ParkHee-Jin HaEun Seon ChungSeung Hyun BaekYoonsuk ChoHark Kyun KimJihoon HanJae Hoon SulJeongmi LeeEunae KimJunsik KimYong Ryoul YangMikyoung ParkSung Hyun KimThiruma V ArumugamHyemin JangSang Won SeoPann-Ghill SuhDong-Gyu JoPublished in: Science advances (2021)
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.
Keyphrases
- protein kinase
- mouse model
- signaling pathway
- end stage renal disease
- chronic kidney disease
- newly diagnosed
- type diabetes
- cognitive decline
- cognitive impairment
- ejection fraction
- cell death
- peritoneal dialysis
- white matter
- inflammatory response
- machine learning
- big data
- metabolic syndrome
- risk assessment
- mild cognitive impairment
- brain injury
- climate change
- artificial intelligence
- risk factors