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

Abstract

<i>O</i>-GlcNAcylation (<i>O</i>-linked β-<i>N</i>-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 <i>O</i>-GlcNAcylation, β-amyloid (Aβ) accumulation, and necroptosis are unclear. Here, we found that <i>O</i>-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 <i>O</i>-GlcNAcylation of RIPK3 (receptor-interacting serine/threonine protein kinase 3) was observed in 5xFAD mice with insufficient <i>O</i>-linked β-<i>N</i>-acetylglucosaminase. <i>O</i>-GlcNAcylation of RIPK3 suppresses phosphorylation of RIPK3 and its interaction with RIPK1. Moreover, increased <i>O</i>-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 <i>O</i>-GlcNAcylation on Aβ accumulation and neurodegeneration, suggesting <i>O</i>-GlcNAcylation-based treatments as potential interventions for AD.