West China School of Pharmacy, Sichuan University, Chengdu 610041, China; Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu 610041, China; Innovation Research Center of Traditional Chinese Medicine and Health Industry, School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China.
Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu 610041, China.
Biomed Pharmacother. 2021 Jul;139:111651. doi: 10.1016/j.biopha.2021.111651. Epub 2021 May 8.
1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (tetrahydrocurcumin, THC) is a major bioactive metabolite of curcumin, demonstrating the potential anti-inflammatory, antioxidant and neuroprotective properties, etc. In this study, it was found that Aβ induced decreased cell viability, cell cycle arrest and apoptosis in BV-2 cells, which were ameliorated by THC. In vivo, THC administration rescued learning and memory, and reduced Aβ burden in the hippocampus of APP/PS1 mice. By proteomic analysis of the hippocampus of mice, 157 differentially expressed proteins were identified in APP/PS1 mice treated with THC (comparing with APP/PS1 mice), which also suggested that the effects of THC on the cell cycle and apoptosis were mostly related to the "Ras signaling pathway", etc. In APP/PS1 mice, the down-regulation of Gab2 and K-Ras, and the up-regulation of caspase-3, TGF-β1 and TNF-ɑ were observed; THC attenuated the abnormal expression of Gab2, K-Ras, caspase-3 and TNF-ɑ, and up-regulated TGF-β1 and Bag1 expression. In BV-2 cells, Aβ induced the down-regulation of Gab2, K-Ras and TGF-β1, and the overexpression of caspase-3, PARP1, cleaved-PARP1 and TNF-ɑ, which were restored by THC. Moreover, THC up-regulated Bag1 expression in Aβ-treated BV-2 cells. The decreased transcriptional expression of Ccnd2 and Cdkn1a were also observed in Aβ-treated BV-2 cells, and THC alleviated the down-regulation of Ccnd2. For the first time, we identified that the action of THC in preventing AD was associated with inhibition of cell cycle arrest and apoptosis of microglia via the Ras/ERK signaling pathway, shedding new light on the role of THC in alleviating the progression of AD.
1,7-双(4-羟基-3-甲氧基苯基)庚烷-3,5-二酮（四氢姜黄素，THC）是姜黄素的主要生物活性代谢物，具有潜在的抗炎、抗氧化和神经保护等特性。在这项研究中，发现 Aβ 诱导 BV-2 细胞活力降低、细胞周期停滞和凋亡，而 THC 可改善这些情况。体内实验中，THC 给药可挽救 APP/PS1 小鼠的学习记忆能力，并减少海马 Aβ 负荷。通过对 THC 处理的 APP/PS1 小鼠海马的蛋白质组学分析，共鉴定出 157 种差异表达蛋白（与 APP/PS1 小鼠相比），这也表明 THC 对细胞周期和凋亡的影响主要与“Ras 信号通路”等有关。在 APP/PS1 小鼠中，观察到 Gab2 和 K-Ras 下调，caspase-3、TGF-β1 和 TNF-ɑ 上调；THC 减弱了 Gab2、K-Ras、caspase-3 和 TNF-ɑ 的异常表达，并上调了 TGF-β1 和 Bag1 的表达。在 Aβ 诱导的 BV-2 细胞中，Gab2、K-Ras 和 TGF-β1 下调，caspase-3、PARP1、cleaved-PARP1 和 TNF-ɑ 过表达，而 THC 可恢复这些异常表达。此外，THC 还可上调 Aβ 处理的 BV-2 细胞中 Bag1 的表达。Aβ 处理的 BV-2 细胞中 Ccnd2 和 Cdkn1a 的转录表达也降低，而 THC 缓解了 Ccnd2 的下调。我们首次发现，THC 预防 AD 的作用与通过 Ras/ERK 信号通路抑制小胶质细胞的细胞周期停滞和凋亡有关，这为 THC 缓解 AD 进展的作用提供了新的视角。
