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

摘要: O-GlcNAcylation (O-linked β-N-acetylglucosaminylation) is notably decreased in Alzheimer's disease (AD) brain. Necroptosis activated AD brain and positively correlated with neuroinflammation tau pathology. However, the links among altered O-GlcNAcylation, β-amyloid (Aβ) accumulation, necroptosis are unclear. Here, we found that plays a protective role by inhibiting necroptosis. was increased patients mouse model compared controls; however, due to of RIPK3 (receptor-interacting serine/threonine protein kinase 3) observed 5xFAD mice insufficient O-linked β-N-acetylglucosaminase. suppresses phosphorylation its interaction RIPK1. Moreover, ameliorated pathology, including Aβ burden, neuronal loss, neuroinflammation, damaged mitochondria recovered M2 phenotype phagocytic activity microglia. Thus, our data establish influence on accumulation neurodegeneration, suggesting O-GlcNAcylation-based treatments as potential interventions for AD.