Li Meiting, Cai Nan, Gu Liang, Yao Lijun, Bi Decheng, Fang Weishan, Lin Zhijian, Wu Yan, Xu Hong, Li Hui, Hu Zhangli, Xu Xu
Shenzhen Key Laboratory of Marine Bioresources and Ecology, Guangdong Provincial Key Laboratory for Plant Epigenetics, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518060, People's Republic of China.
Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, People's Republic of China.
Mol Neurobiol. 2021 Aug;58(8):4134-4144. doi: 10.1007/s12035-021-02389-8. Epub 2021 May 4.
Alzheimer's disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aβ) production or removing these molecules is considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aβ generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3β, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aβ production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aβ generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD.
阿尔茨海默病（AD）是一种具有神经原纤维缠结和淀粉样斑块特征的毁灭性脑部疾病。抑制 Tau 蛋白和β淀粉样蛋白（Aβ）的产生或清除这些分子被认为是 AD 的潜在治疗策略。京尼平是一种苷元，从栀子果实提取物中分离得到。在本研究中，研究了京尼平对抑制 Tau 聚集和 Aβ生成的作用及其分子机制。结果表明，京尼平与 Tau 结合并防止肝素诱导的 Tau 纤维形成。此外，京尼平可能通过下调 CDK5 和 GSK-3β的表达来抑制 Tau 磷酸化，并在 Tau 过表达细胞中通过 SIRT1/LKB1/AMPK 信号通路激活 mTOR 依赖性自噬。此外，京尼平在 N2a/SweAPP 细胞中通过 PERK/eIF2α信号通路抑制 BACE1 的表达，从而减少 Aβ的产生。这些数据表明，京尼平在体外可有效导致磷酸化 Tau 水平和 Aβ生成显著降低，提示京尼平可能被开发成为预防 AD 的有效治疗补充剂或潜在的营养保健品。
