Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
Biochem Pharmacol. 2020 Jul;177:113997. doi: 10.1016/j.bcp.2020.113997. Epub 2020 Apr 27.
Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder with complex pathogenesis. The fibrillar peptide β-amyloid (Aβ) has a chief function in the pathogenesis of AD. Emerging evidence has indicated that there is a tight relationship between inflammation, mitochondrial dysfunction and Aβ formation. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. Recent research corroborated the beneficial roles of TSG in alleviating the learning and memory of AD models. Unfortunately, the underlying mechanism of TSG remains poorly elucidated. The purpose of the present study was to investigate the effects of TSG on LPS/ATP and Aβ-induced inflammation in microglia and neurons and its underlying molecular mechanisms. Our results found that treatment with TSG significantly attenuated the secretion of inflammatory cytokines, reduced NLRP3 inflammasome, and regulated mitophagy. TSG efficiently alleviated LPS-induced inflammatory response by inhibiting the NLRP3 signaling pathway both in microglia and neuron. Meanwhile, TSG promoted autophagy involved in the AMPK/PINK1/Parkin signaling pathway, which may contribute to the protective activity. Additional mechanistic investigations to evaluate the dependence of the neuroprotective role of TSG on PINK1 revealed that a lack of PINK1 inhibited autophagy, especially mitophagy in microglia. Importantly, knockdown of PINK1 or Parkin by siRNA or CRISPR/Cas9 system abolished the protective effects of TSG. In conclusion, these phenomena suggested that TSG prevented LPS/ATP and Aβ-induced inflammation via AMPK/PINK1/Parkin-dependent enhancement of mitophagy. We found the neuroprotective effect of TSG, suggesting it may be beneficial for AD prevention and treatment by suppressing the activation of inflammation.
阿尔茨海默病（AD）是一种不可逆的神经退行性脑疾病，具有复杂的发病机制。纤维状肽β-淀粉样蛋白（Aβ）在 AD 的发病机制中起主要作用。新出现的证据表明，炎症、线粒体功能障碍和 Aβ形成之间存在紧密关系。2,3,5,4'-四羟基二苯乙烯-2-O-β-D-葡萄糖苷（TSG）是从何首乌中提取的主要活性成分之一。最近的研究证实了 TSG 在缓解 AD 模型学习和记忆方面的有益作用。不幸的是，TSG 的潜在机制仍未得到充分阐明。本研究旨在探讨 TSG 对 LPS/ATP 和 Aβ诱导的小胶质细胞和神经元炎症的影响及其潜在的分子机制。我们的研究结果发现，TSG 治疗可显著减轻炎症细胞因子的分泌，减少 NLRP3 炎性体，并调节线粒体自噬。TSG 通过抑制 NLRP3 信号通路，在小胶质细胞和神经元中均能有效缓解 LPS 诱导的炎症反应。同时，TSG 促进 AMPK/PINK1/Parkin 信号通路参与的自噬，这可能有助于发挥保护作用。进一步的机制研究评估了 TSG 神经保护作用对 PINK1 的依赖性表明，缺乏 PINK1 抑制自噬，特别是小胶质细胞中的线粒体自噬。重要的是，siRNA 或 CRISPR/Cas9 系统敲低 PINK1 或 Parkin 可消除 TSG 的保护作用。总之，这些现象表明，TSG 通过 AMPK/PINK1/Parkin 依赖性增强线粒体自噬来防止 LPS/ATP 和 Aβ 诱导的炎症。我们发现 TSG 的神经保护作用，表明通过抑制炎症的激活，它可能有益于 AD 的预防和治疗。
