title: Gypenoside XVII Enhances Lysosome Biogenesis and Autophagy Flux and Accelerates Autophagic Clearance of Amyloid-β through TFEB Activation.
abstract: A strategy for activating transcription factor EB (TFEB) to restore autophagy flux may provide neuroprotection against Alzheimer's disease. Our previous study reported that gypenoside XVII (GP-17), which is a major saponin abundant in ginseng and Panax notoginseng, ameliorated amyloid-β (Aβ)25-35-induced apoptosis in PC12 cells by regulating autophagy. In the present study, we aimed to determine whether GP-17 has neuroprotective effects on PC12 cells expressing the Swedish mutant of APP695 (APP695swe) and APP/PS1 mice. We also investigated the underlying mechanism. We found that GP-17 could significantly increase Atg5 expression and the conversion of LC3-I to LC3-II in APP695 cells, which was associated with a reduction in p62 expression. GP-17 also elevated the number of LC3 puncta in APP695 cells transduced with pCMV-GFP-LC3. GP-17 promoted the autophagy-based elimination of AβPP, Aβ40, and Aβ42 in APP695swe cells and prevented the formation of Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Furthermore, spatial learning and memory deficits were cured. Atg5 knockdown could abrogate the GP-17-mediated removal of AβPP, Aβ40, and Aβ42 in APP695swe cells. GP-17 upregulated LAMP-1, increased LysoTracker staining, and augmented LAMP-1/LC3-II co-localization. GP-17 could release TFEB from TFEB/14-3-3 complexes, which led to TFEB nuclear translocation and the induction of autophagy and lysosome biogenesis and resulted in the amelioration of autophagy flux. The knockdown of TFEB could abolish these effects of GP-17. In summary, these results demonstrated that GP-17 conferred protective effects to the cellular and rodent models of Alzheimer's disease by activating TFEB.
authors.affiliation: Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, PR China.
authors.forename: Xiangbao
authors.initials: X
authors.lastname: Meng
authors.affiliation: Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Center of Research on Life Science and Environmental Science, Harbin University of Commerce, Harbin, PR China.
authors.forename: Tian
authors.initials: T
authors.lastname: Liang
authors.affiliation: Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Mengxia
authors.initials: M
authors.lastname: Wang
authors.affiliation: Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, PR China.
authors.forename: Guibo
authors.initials: G
authors.lastname: Sun
authors.affiliation: Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, PR China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Sun
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000588:Amines / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D029774:Gynostemma; D008247:Lysosomes / Q000187:drug effects* / Q000648:ultrastructure; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016716:PC12 Cells; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D051381:Rats
chemical_list: D000588:Amines; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000071187:Autophagy-Related Protein 5; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C508853:PSEN1 protein, human; D010936:Plant Extracts; D053764:Presenilin-1; C493330:Red DND-99; C574124:TFEB protein, rat; C474918:gypenoside; C025946:3-methyladenine; D000225:Adenine
keywords: APP/PS1 mice; autophagy flux; lysosome biogenesis; transcription factor EB