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

Sci Adv. 2021 Jan 13;7(3):eabd3207. doi: 10.1126/sciadv.abd3207. Print 2021 Jan.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / metabolism
  • Humans
  • Mice
  • Necroptosis
  • Phosphorylation


  • Amyloid beta-Peptides