自噬
秀丽隐杆线虫
生物
神经保护
RNA干扰
神经退行性变
程序性细胞死亡
基因敲除
PI3K/AKT/mTOR通路
细胞生物学
药理学
疾病
细胞凋亡
生物化学
医学
基因
信号转导
病理
核糖核酸
作者
Tao Long,Xue Chen,Da‐Lian Qin,Yunfei Zhu,Yu-Jia Zhou,Yan-Ni He,Hailing Fu,Yong Tang,Lu Yu,Feihong Huang,Long Wang,Chong‐Lin Yu,Betty Yuen‐Kwan Law,Jianming Wu,Anguo Wu,Xiaogang Zhou
摘要
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder without an effective cure. Natural products, while showing promise as potential therapeutics for AD, remain underexplored.This study was conducted with the goal of identifying potential anti-AD candidates from natural sources using Caenorhabditis elegans (C. elegans) AD-like models and exploring their mechanisms of action.Our laboratory's in-house herbal extract library was utilized to screen for potential anti-AD candidates using the C. elegans AD-like model CL4176. The neuroprotective effects of the candidates were evaluated in multiple C. elegans AD-like models, specifically targeting Aβ- and Tau-induced pathology. In vitro validation was conducted using PC-12 cells. To investigate the role of autophagy in mediating the anti-AD effects of the candidates, RNAi bacteria and autophagy inhibitors were employed.The ethanol extract of air-dried fruits of Luffa cylindrica (LCE), a medicine-food homology species, was found to inhibit Aβ- and Tau-induced pathology (paralysis, ROS production, neurotoxicity, and Aβ and pTau deposition) in C. elegans AD-like models. LCE was non-toxic and enhanced C. elegans' health. It was shown that LCE activates autophagy and its anti-AD efficacy is weakened with the RNAi knockdown of autophagy-related genes. Additionally, LCE induced mTOR-mediated autophagy, reduced the expression of AD-associated proteins, and decreased cell death in PC-12 cells, which was reversed by autophagy inhibitors (bafilomycin A1 and 3-methyladenine).LCE, identified from our natural product library, emerged as a valuable autophagy enhancer that effectively protects against neurodegeneration in multiple AD-like models. RNAi knockdown of autophagy-related genes and cotreatment with autophagy inhibitors weakened its anti-AD efficacy, implying a critical role of autophagy in mediating the neuroprotective effects of LCE.Our findings highlight the potential of LCE as a functional food or drug for targeting AD pathology and promoting human health.
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