Alpha7 nicotinic acetylcholine receptor is required for amyloid pathology in brain endothelial cells induced by Glycoprotein 120, methamphetamine and nicotine.
Alpha7 nicotinic acetylcholine receptor is required for amyloid pathology in brain endothelial cells induced by Glycoprotein 120, methamphetamine and nicotine.
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DOI：
10.1038/srep40467
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发表时间：
2017-01-11
影响因子：
4.6
通讯作者：
Huang SH
中科院分区：
文献类型：
--
作者：
Liu L;Yu J;Li L;Zhang B;Liu L;Wu CH;Jong A;Mao DA;Huang SH
由HIV-1病毒毒素和药物滥用引起的HIV相关性神经认知障碍(HAND)最具挑战性的问题之一是缺乏对通常与血脑屏障(BBB)障碍相关的潜在机制的了解，血脑屏障主要由脑微血管内皮细胞(BMEC)组成。在这里，我们假设糖蛋白120(Gp120)、甲基苯丙胺(METH)和尼古丁(NT)可以通过α7烟碱型乙酰胆碱受体(β7nAChR)增加淀粉样β蛋白(Aα)在骨髓内皮细胞中的积聚。采用体外培养的人脐静脉内皮细胞和体内的小鼠血脑屏障模型，观察α7nAChR在gp12 0、冰毒和NT诱导的Aβ表达上调中的作用。这些因素显著增加了β的释放和跨HBMEC的转运。α7nAChR拮抗剂甲基乌头碱可有效阻断上述致病效应。动物实验表明，这些因素可显著提高小鼠脑脊液中Aβ、Tau和泛素C末端水解酶1(UCHL1)以及小鼠脑中Aβ的水平。α-7nAChR可能在gp120、METH和NT引起的神经病理中起重要作用，而gp120、METH和NT是Hand发病的主要致病因素。
One of the most challenging issues in HIV-associated neurocognitive disorders (HAND) caused by HIV-1 virotoxins and drug abuse is the lack of understanding the underlying mechanisms that are commonly associated with disorders of the blood-brain barrier (BBB), which mainly consists of brain microvascular endothelial cells (BMEC). Here, we hypothesized that Glycoprotein 120 (gp120), methamphetamine (METH) and nicotine (NT) can enhance amyloid-beta (Aβ) accumulation in BMEC through Alpha7 nicotinic acetylcholine receptor (α7 nAChR). Both in vitro (human BMEC) (HBMEC) and in vivo (mice) models of BBB were used to dissect the role of α7 nAChR in up-regulation of Aβ induced by gp120, METH and NT. Aβ release from and transport across HBMEC were significantly increased by these factors. Methyllycaconitine (MLA), an antagonist of α7 nAChR, could efficiently block these pathogenic effects. Furthermore, our animal data showed that these factors could significantly increase the levels of Aβ, Tau and Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in mouse cerebrospinal fluid (CSF) and Aβ in the mouse brains. These pathogenicities were significantly reduced by MLA, suggesting that α7 nAChR may play an important role in neuropathology caused by gp120, METH and NT, which are the major pathogenic factors contributing to the pathogenesis of HAND.