2. Academic Validation
  3. NPLC0393 from Gynostemma pentaphyllum ameliorates Alzheimer's disease-like pathology in mice by targeting protein phosphatase magnesium-dependent 1A phosphatase

NPLC0393 from Gynostemma pentaphyllum ameliorates Alzheimer's disease-like pathology in mice by targeting protein phosphatase magnesium-dependent 1A phosphatase

  • Phytother Res. 2023 Jul 11. doi: 10.1002/ptr.7945.
Jianlu Lv 1 2 3,  Xingyi Shen 1 2,  Xinya Shen 1 2,  Shimei Zhao 1 2,  Rui Xu 1 2,  Qiuying Yan 1 2,  Jian Lu 1 2,  Danyang Zhu 1 2,  Yonghua Zhao 4,  Jiajia Dong 3,  Jiaying Wang 1 2,  Xu Shen 1 2 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China.
  • 2 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  • 3 College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
  • 4 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
  • 5 National Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing, China.
PMID: 37434441 DOI: 10.1002/ptr.7945
Abstract

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 3×Tg-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 3×Tg-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 3×Tg-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-κB/CX3CR1 pathway. PPM1A mediates microglia/neurons crosstalk in AD pathology, whose activation by NPLC0393 represents a promising therapeutic strategy for AD.

Keywords

AD; Gynostemma pentaphyllum; NLRP3; NPLC0393; PPM1A; tau.

Figures
Products