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

Abstract

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