Resveratrol Abrogates Hypoxia-Induced Up-Regulation of Exosomal Amyloid- Partially by Inhibiting CD147
Resveratrol Abrogates Hypoxia-Induced Up-Regulation of Exosomal Amyloid- Partially by Inhibiting CD147
复制标题
白藜芦醇部分通过抑制 CD147 消除缺氧诱导的外泌体淀粉样蛋白上调
DOI：
10.1007/s11064-019-02742-3
复制
发表时间：
2019
影响因子：
4.4
通讯作者：
Zhao Yanxin
中科院分区：
文献类型：
--
作者：
Xie Junchao;Li Xiaoyan;Zhou Yuchen;Wu Jiayan;Tan Yan;Ma Xiaoye;Zhao Yichen;Liu Xueyuan;Zhao Yanxin
缺氧可促进细胞外和外泌体淀粉样蛋白β（Aβ）的生成，从而导致阿尔茨海默病（AD）的发生。白藜芦醇（Resveratrol，RSV）对AD模型具有神经保护作用，并下调γ-分泌酶亚基CD 147的表达。本研究旨在探讨呼吸道合胞病毒（RSV）在缺氧诱导的Aβ（尤其是exosomal Aβ）表达上调中的作用及其机制。用RSV处理过表达淀粉样前体蛋白（APP）的SH-SY 5 Y细胞和HEK 293细胞以及C57 BL/6小鼠，并暴露于缺氧条件。SIRT 1或CD 147的表达通过特异性siRNA或质粒的转染来调节。采用ELISA法测定Aβ1-40和Aβ1-42水平。缺氧可增加小鼠海马裂解物和血清来源外泌体中Aβ1-40和Aβ1-42的水平。缺氧还增加了两种细胞系的总培养基（CM）、细胞源性外泌体裂解物和无外泌体CM中的Aβ1-40和Aβ1-42水平。RSV治疗可消除Aβ表达的这些变化，抑制缺氧诱导的SIRT 1下调和CD 147上调。SIRT 1基因敲除可提高总Aβ水平，但对外泌体Aβs表达无影响。CD 147的敲低抑制总A β和外泌体Aβ的表达。此外，在暴露于缺氧的细胞中过表达CD 147促进了Aβ1-40和Aβ1-42的产生，而RSV的应用降低了外泌体和无外泌体CM中的CD 147表达以及Aβ水平。这些结果表明，RSV通过抑制CD 147部分地消除了缺氧诱导的总A β和外泌体Aβ的上调。
Hypoxia promotes both total extracellular and exosomal amyloid-β (Aβ) production and aggravates Alzheimer’s disease (AD). Resveratrol (RSV) has been proved to be neuroprotective in AD models, and down-regulated the expression of CD147, an additional subunit of γ-secretase. In this study, we aimed to explore the role and mechanisms of RSV in hypoxia-induced upregulation of Aβ, especially exosomal Aβ. SH-SY5Y cells and HEK293 cells overexpressing amyloid precursor protein (APP) as well as C57BL/6 mice were treated with RSV and exposed to hypoxic conditions. The expression of SIRT1 or CD147 was modulated by transfection of specific siRNAs or plasmid. Aβ1-40 and Aβ1-42 levels were determined by ELISA. Hypoxia increased the levels of both Aβ1-40 and Aβ1-42 in the hippocampal lysates and serum-derived exosomes of mice. Hypoxia also increased both Aβ1-40 and Aβ1-42 levels in the total culture medium (CM), cell-derived exosomal lysates, and exosome-free CM of both cell lines. Treatment with RSV abrogated these changes in Aβ expression, inhibited the hypoxia-induced down-regulation of SIRT1 and up-regulation of CD147. Knockdown of SIRT1 promote total Aβ level but has no effect on exosomal Aβs expression. Knockdown of CD147 inhibits both total and exosomal Aβs expression. Furthermore, overexpressing CD147 in cells exposed to hypoxia facilitated the production of Aβ1-40 and Aβ1-42, while application of RSV reduced the CD147 expression as well as Aβ levels in both exosomes and exosome-free CM. These results suggested that RSV abrogated hypoxia-induced up-regulation of total and exosomal Aβ partially by inhibiting CD147.