中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (11): 2467-2479.doi: 10.4103/NRR.NRR-D-23-00954

• 原著:退行性病与再生 • 上一篇    下一篇

橘核提取物改善淀粉样β蛋白诱导的神经细胞死亡和认知障碍:激活自噬作用

  

  • 出版日期:2024-11-15 发布日期:2024-03-29
  • 基金资助:
    中国澳门科学技术发展基金 FDCT;佛山医药登峰项目 2019-2021;四川省科技计划;四川省中医药委员会;泸州市科技计划;西南医科大学科技计划

Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease

Yong Tang1, 2, #, Jing Wei3, #, Xiao-Fang Wang4, #, Tao Long2, Xiaohong Xiang5, Liqun Qu1, Xingxia Wang1, Chonglin Yu4, Xingli Xiao6, Xueyuan Hu2, Jing Zeng2, Qin Xu5, Anguo Wu2, Jianming Wu4, Dalian Qin2, *, Xiaogang Zhou2, *, Betty Yuen-Kwan Law1,*   

  1. 1Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao Special Administrative Region, China; 2Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, Sichuan Province, China; 3Eye School and Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection of Chengdu University of TCM, Chengdu, Sichuan Province, China; 4School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan Province, China; 5Department of Ophthalmology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China; 6Department of Neurology, The First People’s Hospital of Neijiang, Neijiang, Sichuan Province, China
  • Online:2024-11-15 Published:2024-03-29
  • Contact: Betty Yuen-Kwan Law, PhD, yklaw@must.edu.mo; Xiaogang Zhou, PhD, zxg@swmu.edu.cn; Dalian Qin, MD, dalianqin@swmu.edu.cn.
  • Supported by:
    This study was supported by FDCT grants from the Macao Science and Technology Development Fund, China, No. 002/2023/ALC (to BYKL); Foshan Medicine Dengfeng Project of China 2019–2021 (to BYKL); the Science and Technology Program of Sichuan Province, Nos. 2022YFS0620 (to DQ) and MZGC20230041 (to XFW); the TCMs Commission of Sichuan Province, No. 2021MS469 (to YT); the Science and Technology Program of Luzhou, No. 2022-WGR-194 (to YT); and the Southwest Medical University Science and Technology Program, No. 2021NJXNYD04 (to DQ).

摘要:

淀粉样β蛋白诱导的神经细胞死亡是阿尔茨海默病认知能力下降的原因之一。橘核对包括帕金森病和亨廷顿病在内的神经退行性疾病有多种有益作用,但其对阿尔茨海默病的作用仍未阐明。实验首先研究了橘核提取物对淀粉样β蛋白诱导的 PC12 细胞凋亡的抗凋亡和自噬作用。橘核提取物通过激活自噬降低 Bax/Bcl-2 比率,从而保护 PC12 细胞免受淀粉样β蛋白诱导的凋亡。体外生物层干涉测量法证实橘核提取物能结合淀粉样β蛋白,并能在转基因秀丽隐杆线虫体内模型中抑制淀粉样β蛋白诱导的病理变化。橘核提取物对有遗传缺陷的秀丽隐杆线虫的神经保护作用依赖于自噬。最重要的是,橘核提取物能改善 3xTg阿尔茨海默病小鼠的认知障碍、神经元损伤和减轻淀粉样β蛋白负荷。这些结果表明橘核提取物通过激活自噬作用起到神经保护作用,是一种可用于治疗阿尔茨海默病的潜在药物。

https://orcid.org/0000-0002-8926-3960 (Betty Yuen-Kwan Law); https://orcid.org/0000-0002-2574-3973 (Xiaogang Zhou); 
https://orcid.org/0000-0002-1235-7328 (Dalian Qin)

Abstract: Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer’s disease. Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases, including Parkinson’s and Huntington’s diseases, however, the effect of Citri Reticulatae Semen on Alzheimer’s disease remains unelucidated. In the current study, the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated. Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy. In addition, Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro, and suppress amyloid-beta-induced pathology such as paralysis, in a transgenic Caenorhabditis elegans in vivo model. Moreover, genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent. Most importantly, Citri Reticulatae Semen extract was confirmed to improve cognitive impairment, neuronal injury and amyloid-beta burden in 3×Tg Alzheimer’s disease mice. As revealed by both in vitro and in vivo models, these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer’s disease via its neuroprotective autophagic effects.

Key words: Alzheimer’s disease, amyloid-beta, apoptosis, autophagy, Caenorhabditis elegans, Citri Reticulatae Semen