OBJECTIVE Diabetes mellitus (DM) can increase the risk of cognitive dysfunction, but its exact mechanisms remain unclear. The involvement of aberrant O-GlcNAcylation has been identified in hyperglycemia and DM, as well as the pathogenesis of Alzheimer's disease via competition with tau phosphorylation. This study was designed to investigate the role of O-GlcNAcylation in diabetes-associated cognitive dysfunction (DACD). METHODS Fifteen-week old male KK-Ay mice were used as DACD models, and advanced glycation end product (AGE)-treated HT22 cells were used as a model of high glucose toxicity. Morris water maze tests, histological staining, real-time quantitative PCR, and Western blot were also applied. RESULTS Mice with DACD exhibited evident obesity, hyperinsulinemia, hyperglycemia, and impaired learning and memory function. O-GlcNAcylation levels decreased and tau phosphorylation levels at Ser396, Ser404, Thr212, and Thr231 increased in the hippocampus of mice with DACD, as well as in AGE-treated HT22 cells. Hypoglycemic therapy improved these anomalies and elevated O-GlcNAc transferase (OGT) levels in mice with DACD. OGT plasmid transfection in HT22 cells partially reversed AGE-induced decreases in O-GlcNAcylation levels and increased tau phosphorylation levels. CONCLUSIONS Chronic hyperglycemia can induce tau hyperphosphorylation by downregulating OGT-involved O-GlcNAcylation in vivo and in vitro, which mediates DACD.

中文翻译：

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慢性高血糖通过在体内和体外下调 OGT 相关的 O-GlcNAcylation 来诱导 tau 过度磷酸化。

目的 糖尿病 (DM) 可增加认知功能障碍的风险，但其确切机制尚不清楚。异常的 O-GlcNAcylation 参与高血糖症和 DM，以及通过与 tau 磷酸化竞争引起的阿尔茨海默病的发病机制。本研究旨在研究 O-GlcNAcylation 在糖尿病相关认知功能障碍 (DACD) 中的作用。方法 15 周龄雄性 KK-Ay 小鼠用作 DACD 模型，晚期糖基化终产物 (AGE) 处理的 HT22 细胞用作高葡萄糖毒性模型。还应用了莫里斯水迷宫测试、组织学染色、实时定量 PCR 和蛋白质印迹。结果 DACD 小鼠表现出明显的肥胖、高胰岛素血症、高血糖以及学习和记忆功能受损。在 DACD 小鼠的海马以及 AGE 处理的 HT22 细胞中，O-GlcNAcylation 水平降低，而 Ser396、Ser404、Thr212 和 Thr231 的 tau 磷酸化水平增加。低血糖治疗改善了这些异常并提高了 DACD 小鼠的 O-GlcNAc 转移酶 (OGT) 水平。HT22 细胞中的 OGT 质粒转染部分逆转了 AGE 诱导的 O-GlcNAcylation 水平下降和 tau 磷酸化水平增加。结论 慢性高血糖可以通过在体内和体外下调 OGT 参与的 O-GlcNAcylation 来诱导 tau 过度磷酸化，从而介导 DACD。低血糖治疗改善了这些异常并提高了 DACD 小鼠的 O-GlcNAc 转移酶 (OGT) 水平。HT22 细胞中的 OGT 质粒转染部分逆转了 AGE 诱导的 O-GlcNAcylation 水平下降和 tau 磷酸化水平增加。结论 慢性高血糖可以通过在体内和体外下调 OGT 参与的 O-GlcNAcylation 来诱导 tau 过度磷酸化，从而介导 DACD。低血糖治疗改善了这些异常并提高了 DACD 小鼠的 O-GlcNAc 转移酶 (OGT) 水平。HT22 细胞中的 OGT 质粒转染部分逆转了 AGE 诱导的 O-GlcNAcylation 水平下降和 tau 磷酸化水平增加。结论 慢性高血糖可以通过在体内和体外下调 OGT 参与的 O-GlcNAcylation 来诱导 tau 过度磷酸化，从而介导 DACD。