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.

在阿尔茨海默病 (AD) 脑中，O - GlcNAcylation ( O -linked β- N -acetylglucosaminylation) 显着降低。坏死性凋亡在 AD 脑中被激活，并且与神经炎症和 tau 病理呈正相关。然而，改变的O -GlcNAcylation、β-淀粉样蛋白 (Aβ) 积累和坏死性凋亡之间的联系尚不清楚。在这里，我们发现O -GlcNAcylation 通过抑制坏死性凋亡在 AD 中发挥保护作用。与对照组相比，AD 患者和 AD 小鼠模型的坏死性凋亡增加；然而，在O不足的 5xFAD 小鼠中观察到由于 RIPK3（受体相互作用的丝氨酸/苏氨酸蛋白激酶 3）的O -GlcNAcylation 导致的坏死性凋亡减少-连接的β- N-乙酰氨基葡萄糖酶。RIPK3 的O -GlcNAcylation 抑制 RIPK3 的磷酸化及其与 RIPK1 的相互作用。此外，增加的O -GlcNAcylation 改善了 AD 病理，包括 Aβ 负荷、神经元丢失、神经炎症和线粒体受损，并恢复了小胶质细胞的 M2 表型和吞噬活性。因此，我们的数据确定了O -GlcNAcylation 对 Aβ 积累和神经变性的影响，表明基于O -GlcNAcylation 的治疗是 AD 的潜在干预措施。