SMU‐A inhibits Aβ‐induced NLRP3 inflammasome via autophagy mediated by the AMPK/ULK1 and Raf/MEK/ERK pathways in microglia

Accumulation of β‐amyloid (Aβ) and its induced inflammation are recognized as two major pathological features of Alzheimer disease (AD). Autophagy, an intracellular catabolic mechanism, plays a pivotal role in neurodegenerative disease for degrading the toxic aggregated proteins such as Aβ, α‐Synuclein and mHtt. Recently, autophagy activation in microglia was reported to not only degrade extracellular Aβ fribils but also inhibit Aβ‐induced NLRP3 inflmmasome. In the present experiment, the potential autophagy inducers from SMU, a traditional Chinese medicine, were identified in microglial cells (BV‐2) by using column chromatography, UHPLC‐TOF/MS and NMR technologies. Total four ellagitannin flavonoids including SMU‐A, SMU‐B, SMU‐C and SMU‐D were identified, and SMU‐A was proved to possess the best autophagic effect in BV‐2 cells. Furthermore, the autophagy was activated through the AMPK/ULK1, Raf/MEK/ERK and ATG7 dependent, but independent of mTOR signaling pathway. In Aβ1‐42 induced BV‐2 cells, SMU‐A inhibits inflammasome containing NLRP3, ASC, IL‐1β and caspase1 via autophagy, which was reversed by the autophagic inhibitors such as compound C, SCH772984, hydroxychloroquine and SBI‐0206965. Additionally, SMU‐A can improve cell viability of PC12 induced injury by cell culture medium of Aβ‐induced BV‐2. Taken together, enhanced microglial autophagy is a promising new therapeutic strategy for AD, and demonstrate the autophagy inducers in SMU exerts the potential neuroprotective mechanism in suppressing neuroinflammatory responses by enhancing autophagy in microglial. Therefore, uncovering the components in SMU contributing to autophagy activation and its molecular mechanism provide new insight of PCP into novel therapies for the amelioration of AD. Support or Funding Information The Science and Technology Program of Luzhou” (grant numbers 2016LZXNYD‐T03 and 2017LZXNYD‐J28), “Educational Commission of Sichuan Province” (grant numbers 18ZA0528 and 18TD0051), “Science and Technology Planning Project of Sichuan Province” (grant numbers 2018JY0474 and 2018JY0237) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .