Shi Yachen, Wang Pan, Deng Jingyu, Chen Yunuo, Wang Feng, Han Yan, Wang Hui, Li Yang, Fang Xiangming, Hui Jiaojie, Xi Guangjun
Department of Neurology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Nanjing Medical University, No. 299 Qingyang Road, Wuxi, 214023, PR China.
Department of Radiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, China.
Alzheimers Res Ther. 2025 Aug 22;17(1):196. doi: 10.1186/s13195-025-01846-z.
Growing evidence has suggested that elevated Trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite, are closely associated with brain aging and cognitive impairment. Glycogen synthase kinase-3 beta (GSK-3β) activity was depicted to be essential in regulating learning and memory. The current study examined the impact of TMAO on cognitive function in mild cognitive impairment (MCI) patients and rat models while exploring the mechanisms regulating the TMAO-induced GSK-3β signaling.
This study recruited 115 MCI patients and 128 healthy controls. All participants underwent neuropsychological assessments. Fasting plasma TMAO was measured using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. The study also explored whether the GSK-3β signaling was involved in cognitive and function deficits linked with elevated TMAO in rat models.
Our results indicated that TMAO plasma levels were elevated in MCI patients compared to healthy controls, depicting a significant association with potential MCI risk. Furthermore, chronic exposure to choline considerably impacted spatial cognitive performance in the Morris water maze task. This reduced the phosphorylation of Ser9 of GSK-3β and the synaptic plasticity-related proteins within the hippocampus, which could be restored by inhibiting TMAO with ABS. In addition, inhibition of GSK-3β by SB216763 significantly prevented the TMAO-induced synaptic damage while decreasing the membrane level of GluA1 and improving hippocampal learning and memory.
These results indicate that TMAO can induce hippocampal-dependent learning and memory ability impairment with deficits in synaptic plasticity by regulating the GSK-3β activity.
越来越多的证据表明，三甲胺 N-氧化物（TMAO）水平升高，这种肠道微生物群依赖性代谢产物，与脑衰老和认知障碍密切相关。糖原合酶激酶-3β（GSK-3β）活性被认为在调节学习和记忆中至关重要。本研究检测了 TMAO 对轻度认知障碍（MCI）患者和大鼠模型认知功能的影响，同时探索调节 TMAO 诱导的 GSK-3β信号传导的机制。
本研究招募了 115 名 MCI 患者和 128 名健康对照者。所有参与者均接受神经心理学评估。使用高效液相色谱与在线电喷雾电离串联质谱法测量空腹血浆 TMAO。该研究还探讨了 GSK-3β信号传导是否参与大鼠模型中与 TMAO 升高相关的认知和功能缺陷。
我们的结果表明，与健康对照者相比，MCI 患者的血浆 TMAO 水平升高，这表明与潜在的 MCI 风险存在显著关联。此外，长期暴露于胆碱会对 Morris 水迷宫任务中的空间认知表现产生显著影响。这降低了海马体内 GSK-3β的 Ser9 磷酸化以及与突触可塑性相关的蛋白质水平，而通过使用 ABS 抑制 TMAO 可以恢复这些水平。此外，SB216763 对 GSK-3β的抑制显著预防了 TMAO 诱导的突触损伤，同时降低了 GluA1 的膜水平并改善了海马体的学习和记忆。
这些结果表明，TMAO 可通过调节 GSK-3β活性诱导海马体依赖性学习和记忆能力受损，并伴有突触可塑性缺陷。
