Chen Fan, Wang Na, Tian Xinyan, Su Juan, Qin Yan, He Rongqiao, He Xiaping
School of Basic Medical Sciences, Dali University, Dali 671003, China.
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100045, China.
Pharmaceutics. 2023 May 23;15(6):1568. doi: 10.3390/pharmaceutics15061568.
Formaldehyde (FA) has been found to induce major Alzheimer's disease (AD)-like features including cognitive impairment, Aβ deposition, and Tau hyperphosphorylation, suggesting that it may play a significant role in the initiation and progression of AD. Therefore, elucidating the mechanism underlying FA-induced neurotoxicity is crucial for exploring more comprehensive approaches to delay or prevent the development of AD. Mangiferin (MGF) is a natural C-glucosyl-xanthone with promising neuroprotective effects, and is considered to have potential in the treatment of AD. The present study was designed to characterize the effects and mechanisms by which MGF protects against FA-induced neurotoxicity. The results in murine hippocampal cells (HT22) revealed that co-treatment with MGF significantly decreased FA-induced cytotoxicity and inhibited Tau hyperphosphorylation in a dose-dependent manner. It was further found that these protective effects were achieved by attenuating FA-induced endoplasmic reticulum stress (ERS), as indicated by the inhibition of the ERS markers, GRP78 and CHOP, and downstream Tau-associated kinases (GSK-3β and CaMKII) expression. In addition, MGF markedly inhibited FA-induced oxidative damage, including Ca overload, ROS generation, and mitochondrial dysfunction, all of which are associated with ERS. Further studies showed that the intragastric administration of 40 mg/kg/day MGF for 6 weeks significantly improved spatial learning ability and long-term memory in C57/BL6 mice with FA-induced cognitive impairment by reducing Tau hyperphosphorylation and the expression of GRP78, GSK-3β, and CaMKII in the brains. Taken together, these findings provide the first evidence that MGF exerts a significant neuroprotective effect against FA-induced damage and ameliorates mice cognitive impairment, the possible underlying mechanisms of which are expected to provide a novel basis for the treatment of AD and diseases caused by FA pollution.
已发现甲醛（FA）可诱发主要的阿尔茨海默病（AD）样特征，包括认知障碍、β淀粉样蛋白（Aβ）沉积和tau蛋白过度磷酸化，这表明它可能在AD的发生和发展中起重要作用。因此，阐明FA诱导神经毒性的潜在机制对于探索更全面的延缓或预防AD发展的方法至关重要。芒果苷（MGF）是一种具有良好神经保护作用的天然C-葡萄糖基黄酮，被认为在AD治疗中具有潜力。本研究旨在表征MGF保护免受FA诱导神经毒性的作用及机制。小鼠海马细胞（HT22）实验结果显示，与MGF共同处理可显著降低FA诱导的细胞毒性，并以剂量依赖的方式抑制tau蛋白过度磷酸化。进一步发现，这些保护作用是通过减轻FA诱导的内质网应激（ERS）实现的，这表现为ERS标志物葡萄糖调节蛋白78（GRP78）和C/EBP同源蛋白（CHOP）以及下游与tau相关的激酶（糖原合成酶激酶3β（GSK-3β）和钙/钙调蛋白依赖性蛋白激酶II（CaMKII））表达受到抑制。此外，MGF显著抑制FA诱导的氧化损伤，包括钙超载、活性氧生成和线粒体功能障碍，所有这些都与ERS相关。进一步研究表明，对FA诱导认知障碍的C57/BL6小鼠每日灌胃40mg/kg的MGF，持续6周，可通过减少大脑中tau蛋白过度磷酸化以及GRP78、GSK-3β和CaMKII的表达，显著改善其空间学习能力和长期记忆。综上所述，这些发现首次证明MGF对FA诱导的损伤具有显著的神经保护作用，并改善小鼠认知障碍，其潜在机制有望为AD及FA污染所致疾病的治疗提供新的依据。
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