Targeting microglial autophagic degradation of the NLRP3 inflammasome for identification of thonningianin A in Alzheimer’s disease

作者：Xiaogang Zhou, Wenqiao Qiu, Lu Yu, Rong Pan, Jin‐Feng Teng, Zhipei Sang, Betty Yuen Kwan Law, Ya Zhao, Li Zhang, Lu Yan, Yong Tang, Xiaolei Sun, Vincent Kam Wai Wong, Chong‐Lin Yu, Jianming Wu, Dalian Qin, Anguo Wu · 发表于：Inflammation and Regeneration · 年份：2022 · DOI：10.1186/s41232-022-00209-7 · 被引用次数：54 · 研究领域：Inflammasome and immune disorders、Autophagy in Disease and Therapy、Genomics, phytochemicals, and oxidative stress

BACKGROUND: NLRP3 inflammasome-mediated neuroinflammation plays a critical role in the pathogenesis and development of Alzheimer's disease (AD). Microglial autophagic degradation not only decreases the deposits of extracellular Aβ fibrils but also inhibits the activation of NRLP3 inflammasome. Here, we aimed to identify the potent autophagy enhancers from Penthorum chinense Pursh (PCP) that alleviate the pathology of AD via inhibiting the NLRP3 inflammasome. METHODS: At first, autophagic activity-guided isolation was performed to identify the autophagy enhancers in PCP. Secondly, the autophagy effect was monitored by detecting LC3 protein expression using Western blotting and the average number of GFP-LC3 puncta per microglial cell using confocal microscopy. Then, the activation of NLRP3 inflammasome was measured by detecting the protein expression and transfected fluorescence intensity of NLRP3, ASC, and caspase-1, as well as the secretion of proinflammatory cytokines. Finally, the behavioral performance was evaluated by measuring the paralysis in C. elegans, and the cognitive function was tested by Morris water maze (MWM) in APP/PS1 mice. RESULTS: Four ellagitannin flavonoids, including pinocembrin-7-O-[4″,6″-hexahydroxydiphenoyl]-glucoside (PHG), pinocembrin-7-O-[3″-O-galloyl-4″,6″-hexahydroxydiphenoyl]-glucoside (PGHG), thonningianin A (TA), and thonningianin B (TB), were identified to be autophagy enhancers in PCP. Among these, TA exhibited the strongest autophagy induct...