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

Title
O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer’s disease by inhibiting necroptosis
Authors
박미경Jinsu ParkHee-Jin HaEun Seon ChungSeung Hyun BaekYoonsuk ChoHark Kyun KimJihoon HanJae Hoon SulJeongmi LeeEunae KimJunsik KimYong Ryoul YangSung Hyun KimThiruma V. ArumugamHyemin JangSang Won SeoPann-Ghill SuhDong-Gyu Jo
Keywords
O-GlcNAcylation; Alzheimer’s disease; necroptosis
Issue Date
2021-01
Publisher
Science Advances
Citation
VOL 7, NO 3, eabd3207
Abstract
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.
URI
http://pubs.kist.re.kr/handle/201004/72735
ISSN
2375-2548
Appears in Collections:
KIST Publication > Article
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