PMID- 37434441 OWN - NLM STAT- Publisher LR - 20231017 IS - 1099-1573 (Electronic) IS - 0951-418X (Linking) VI - 37 IP - 10 DP - 2023 Oct TI - NPLC0393 from Gynostemma pentaphyllum ameliorates Alzheimer's disease-like pathology in mice by targeting protein phosphatase magnesium-dependent 1A phosphatase. PG - 4771-4790 LID - 10.1002/ptr.7945 [doi] AB - Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment and memory loss. Gynostemma pentaphyllum ameliorates cognitive impairment, but the mechanisms remain obscure. Here, we determine the effect of triterpene saponin NPLC0393 from G. pentaphyllum on AD-like pathology in 3xTg-AD mice and elucidate the underlying mechanisms. NPLC0393 was administered daily in vivo by intraperitoneal injection for 3 months and its amelioration on the cognitive impairment in 3xTg-AD mice was assessed by new object recognition (NOR), Y-maze, Morris water maze (MWM), and elevated plus-maze (EPM) tests. The mechanisms were investigated by RT-PCR, western blot, and immunohistochemistry techniques, while verified by the 3xTg-AD mice with protein phosphatase magnesium-dependent 1A (PPM1A) knockdown (KD) through brain-specific injection of adeno-associated virus (AAV)-ePHP-KD-PPM1A. NPLC0393 ameliorated AD-like pathology targeting PPM1A. It repressed microglial NLRP3 inflammasome activation by reducing NLRP3 transcription during priming and promoting PPM1A binding to NLRP3 to disrupt NLRP3 assembly with apoptosis-associated speck-like protein containing a CARD and pro-caspase-1. Moreover, NPLC0393 suppressed tauopathy by inhibiting tau hyperphosphorylation through PPM1A/NLRP3/tau axis and promoting microglial phagocytosis of tau oligomers through PPM1A/nuclear factor-kappaB/CX3CR1 pathway. PPM1A mediates microglia/neurons crosstalk in AD pathology, whose activation by NPLC0393 represents a promising therapeutic strategy for AD. CI - (c) 2023 John Wiley & Sons, Ltd. FAU - Lv, Jianlu AU - Lv J AD - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. AD - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Shen, Xingyi AU - Shen X AD - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Shen, Xinya AU - Shen X AD - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Zhao, Shimei AU - Zhao S AD - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Xu, Rui AU - Xu R AD - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Yan, Qiuying AU - Yan Q AD - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Lu, Jian AU - Lu J AD - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Zhu, Danyang AU - Zhu D AD - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Zhao, Yonghua AU - Zhao Y AUID- ORCID: 0000-0001-8714-0476 AD - State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. FAU - Dong, Jiajia AU - Dong J AD - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Wang, Jiaying AU - Wang J AUID- ORCID: 0000-0002-9720-6181 AD - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. FAU - Shen, Xu AU - Shen X AUID- ORCID: 0000-0002-8683-3446 AD - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China. AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. AD - National Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing, China. LA - eng GR - TD-SWYY-013/Innovative Research Team of Six Talent Peaks Project in Jiangsu Province/ GR - KYCX21_1737/Postgraduate Research & Practice Innovation Program of Jiangsu Province/ GR - NZY81703806/The Natural Science Foundation for Young Scientists of Nanjing University of Chinese Medicine/ GR - 2020YLXK018/The Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine/ GR - 82273930/National Natural Science Foundation of China/ PT - Journal Article DEP - 20230711 PL - England TA - Phytother Res JT - Phytotherapy research : PTR JID - 8904486 SB - IM OTO - NOTNLM OT - AD OT - Gynostemma pentaphyllum OT - NLRP3 OT - NPLC0393 OT - PPM1A OT - tau EDAT- 2023/07/12 06:42 MHDA- 2023/07/12 06:42 CRDT- 2023/07/12 02:33 PHST- 2023/06/20 00:00 [revised] PHST- 2022/10/21 00:00 [received] PHST- 2023/06/23 00:00 [accepted] PHST- 2023/07/12 06:42 [pubmed] PHST- 2023/07/12 06:42 [medline] PHST- 2023/07/12 02:33 [entrez] AID - 10.1002/ptr.7945 [doi] PST - ppublish SO - Phytother Res. 2023 Oct;37(10):4771-4790. doi: 10.1002/ptr.7945. Epub 2023 Jul 11.