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Lychee seed polyphenol inhibits A?-induced activation of NLRP3 inflammasome via the LRP1/AMPK mediated autophagy induction - 27/10/20

Doi : 10.1016/j.biopha.2020.110575 
Wen-Qiao Qiu a, 1 , Rong Pan a, b, 1 , Yong Tang a , Xiao-Gang Zhou a , Jian-Ming Wu a, c , Lu Yu a , Betty Yuen-Kwan Law d , Wei Ai a , Chong-Lin Yu a, b, , Da-Lian Qin a, c, , An-Guo Wu a, c,
a Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, 646000, China 
b Department of Human Anatomy, School of Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China 
c Education Ministry Key Laboratory of Medical Electrophysiology, Southwest Medical University, Luzhou, 646000, China 
d State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China 

Corresponding authors at: Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, 646000, China.Sichuan Key Medical Laboratory of New Drug Discovery and Druggability EvaluationLuzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia MedicaSchool of PharmacyMinistry of Education & Medical Electrophysiological Key Laboratory of Sichuan ProvinceSouthwest Medical UniversityLuzhou646000China

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Highlights

LSP, a bioactive fraction enriching polyphenol from lychee seed, activates autophagy via the LRP1/AMPK-regulated autophagy in BV-2 cells.
LRP1 negatively regulates the NLRP3 inflammasome in Aβ(1-42)-induced BV-2 cells.
LSP inhibits the NLRP3 inflammasome-mediated neuroinflammation in Aβ(1-42)-induced BV-2 cells via the LRP1/AMPK signaling pathway.
LSP improves the cognitive function and inhibits the NLRP3 inflammasome in APP/PS1 mice.

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Abstract

Emerging evidence indicates that the enhancement of microglial autophagy inhibits the NLRP3 inflammasome mediated neuroinflammation in Alzheimer's disease (AD). Meanwhile, low density lipoprotein receptor-related protein 1 (LRP1) highly expressed in microglia is able to negatively regulate neuroinflammation and positively regulate autophagy. In addition, we have previously reported that an active lychee seed fraction enriching polyphenol (LSP) exhibits anti-neuroinflammation in Aβ-induced BV-2 cells. However, its molecular mechanism of action is still unclear. In this study, we aim to investigate whether LSP inhibits the NLRP3 inflammasome mediated neuroinflammation and clarify its molecular mechanism in Aβ-induced BV-2 cells and APP/PS1 mice. The results showed that LSP dose- and time-dependently activated autophagy by increasing the expression of Beclin 1 and LC3II in BV-2 cells, which was regulated by the upregulation of LRP1 and its mediated AMPK signaling pathway. In addition, both the Western blotting and fluorescence microscopic results demonstrated that LSP could significantly suppress the activation of NLRP3 inflammasome by inhibiting the expression of NLRP3, ASC, the cleavage of caspase-1, and the release of IL-1β in Aβ(1-42)-induced BV-2 cells. In addition, the siRNA LRP1 successfully abolished the effect of LSP on the activation of AMPK and its mediated autophagy, as well as the inhibition of NLRP3 inflammasome. Furthermore, LSP rescued PC-12 cells which were induced by the conditioned medium from Aβ(1-42)-treated BV-2 cells. Moreover, LSP improved the cognitive function and inhibited the NLRP3 inflammasome in APP/PS1 mice. Taken together, LSP inhibited the NLRP3 inflammasome-mediated neuroinflammation in the in vitro and in vivo models of AD, which was closely associated with the LRP1/AMPK-mediated autophagy. Thus, the findings from this study further provide evidences for LSP serving as a potential drug for the treatment of AD in the future.

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Chemical compounds studied in this article : LY294002 (PubChem CID: 3973), Compound C (PubChem CID: 11524144), SBI-0206965 (PubChem CID: 92044402), Bafilomycin A1 (PubChem CID: 6436223), AICAR (PubChem CID: 266934), Rapamycin (PubChem CID: 5284616), Thiazolyl blue (PubChem CID: 64965), 4',6-Diamidino-2-phenylindole (PubChem CID: 2954)

Abbreviations : AD, LRP1, CMHs, PD, HD, TCM, tfLC3, FBS, HFIP, WT, AEC, MWM, PFA, OCT, PI, PVDE, SD, CM

Keywords : Lychee seed polyphenol, Alzheimer's disease, Aβ(1-42), NLRP3 inflammasome, LRP1/AMPK, Autophagy


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