Zhu Shanshan, Wang Nan, Chen Shuyang, Zou Ju, Tan Sijie
Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, China.
Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, China; Institute of Traditional Chinese Medicine Health Industry, China Academy of Chinese Medical Sciences, Nanchang, 330115, China.
Neurochem Int. 2025 Sep;188:106014. doi: 10.1016/j.neuint.2025.106014. Epub 2025 Jun 26.
Microglia activation contributed to the development of Parkinson's disease (PD)-associated cognitive impairment and targeting microglia may be a promising strategy for improving the cognitive function in PD. O-GlcNAclytion is a novel protein post-translational modification with cognitive enhancing effects. This study aimed to investigate the effects of Thiamet-G (TMG), an O-GlcNAcase inhibitor that can increase the intracellular O-GlcNAclytion levels, on PD-associated cognitive impairment and the mechanism related to microglia activation. A PD mouse model was established using rotenone (ROT) and the cognitive functions of these mice were investigated by behavioral tests. The anti-inflammatory effects of TMG were tested in the BV2 microglia cells. TMG treatment significantly improved the cognitive function in the ROT-induced PD mouse model as evidenced by the Y-maze test and objective recognition test. Histological studies showed that TMG decreased the reactive microglia via increasing the total protein O-GlcNAclytion levels in the hippocampus of the PD mice. In the in vitro studies, TMG inhibited ROT-induced inflammation via decreasing the pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 in BV2 microglia cells. Bioinformatic analysis revealed that STING, a core protein in the innate immunity regulation, might be a novel target of O-GlcNAclytion. The immunoprecipitation experiments further confirmed that TMG inhibited STING phosphorylation via increasing O-GlcNAcylation. Taken together, TMG might ameliorate PD-associated cognitive impairment via increasing O-GlcNAcylation of STING in microglia, which provided evidence supporting that inhibiting the inflammatory response of microglia by elevating the O-GlcNAclytion levels might be an effective strategy for improving the cognitive function in PD.
小胶质细胞激活促成了帕金森病（PD）相关认知障碍的发展，而靶向小胶质细胞可能是改善PD认知功能的一种有前景的策略。O-连接的N-乙酰葡糖胺糖基化（O-GlcNAcylation）是一种具有认知增强作用的新型蛋白质翻译后修饰。本研究旨在探讨硫胺素-G（TMG），一种可增加细胞内O-GlcNAcylation水平的O-连接的N-乙酰葡糖胺酶抑制剂，对PD相关认知障碍的影响以及与小胶质细胞激活相关的机制。使用鱼藤酮（ROT）建立PD小鼠模型，并通过行为测试研究这些小鼠的认知功能。在BV2小胶质细胞中测试了TMG的抗炎作用。Y迷宫试验和客观识别试验证明，TMG治疗显著改善了ROT诱导的PD小鼠模型的认知功能。组织学研究表明，TMG通过增加PD小鼠海马中总蛋白质O-GlcNAcylation水平来减少反应性小胶质细胞。在体外研究中，TMG通过降低BV2小胶质细胞中促炎细胞因子如TNF-α、IL-1β和IL-6来抑制ROT诱导的炎症。生物信息学分析显示，天然免疫调节中的核心蛋白STING可能是O-GlcNAcylation的一个新靶点。免疫沉淀实验进一步证实，TMG通过增加O-糖基化抑制STING磷酸化。综上所述，TMG可能通过增加小胶质细胞中STING的O-糖基化来改善PD相关认知障碍，这为通过提高O-GlcNAcylation水平抑制小胶质细胞的炎症反应可能是改善PD认知功能的有效策略提供了证据。
