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Gypenoside XVII Enhances Lysosome Biogenesis and Autophagy Flux and Accelerates Autophagic Clearance of Amyloid-β through TFEB Activation.
J Alzheimers Dis. 2016 04 05; 52(3):1135-50.JA

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+Show Affiliations

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.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.Center of Research on Life Science and Environmental Science, Harbin University of Commerce, Harbin, PR China.Guangzhou University of Chinese Medicine, Guangzhou, PR China.Guangzhou University of Chinese Medicine, Guangzhou, PR China.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.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27060963

Citation

Meng, Xiangbao, et al. "Gypenoside XVII Enhances Lysosome Biogenesis and Autophagy Flux and Accelerates Autophagic Clearance of Amyloid-β Through TFEB Activation." Journal of Alzheimer's Disease : JAD, vol. 52, no. 3, 2016, pp. 1135-50.
Meng X, Luo Y, Liang T, et al. Gypenoside XVII Enhances Lysosome Biogenesis and Autophagy Flux and Accelerates Autophagic Clearance of Amyloid-β through TFEB Activation. J Alzheimers Dis. 2016;52(3):1135-50.
Meng, X., Luo, Y., Liang, T., Wang, M., Zhao, J., Sun, G., & Sun, X. (2016). Gypenoside XVII Enhances Lysosome Biogenesis and Autophagy Flux and Accelerates Autophagic Clearance of Amyloid-β through TFEB Activation. Journal of Alzheimer's Disease : JAD, 52(3), 1135-50. https://doi.org/10.3233/JAD-160096
Meng X, et al. Gypenoside XVII Enhances Lysosome Biogenesis and Autophagy Flux and Accelerates Autophagic Clearance of Amyloid-β Through TFEB Activation. J Alzheimers Dis. 2016 04 5;52(3):1135-50. PubMed PMID: 27060963.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gypenoside XVII Enhances Lysosome Biogenesis and Autophagy Flux and Accelerates Autophagic Clearance of Amyloid-β through TFEB Activation. AU - Meng,Xiangbao, AU - Luo,Yun, AU - Liang,Tian, AU - Wang,Mengxia, AU - Zhao,Jingyu, AU - Sun,Guibo, AU - Sun,Xiaobo, PY - 2016/4/11/entrez PY - 2016/4/12/pubmed PY - 2017/7/15/medline KW - APP/PS1 mice KW - autophagy flux KW - lysosome biogenesis KW - transcription factor EB SP - 1135 EP - 50 JF - Journal of Alzheimer's disease : JAD JO - J Alzheimers Dis VL - 52 IS - 3 N2 - 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. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/27060963/Gypenoside_XVII_Enhances_Lysosome_Biogenesis_and_Autophagy_Flux_and_Accelerates_Autophagic_Clearance_of_Amyloid_β_through_TFEB_Activation_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-160096 DB - PRIME DP - Unbound Medicine ER -