Up-regulation of the Neuronal Nicotinic Receptor α7 by HIV Glycoprotein 120 POTENTIAL IMPLICATIONS FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDER
Up-regulation of the Neuronal Nicotinic Receptor α7 by HIV Glycoprotein 120 POTENTIAL IMPLICATIONS FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDER
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DOI：
10.1074/jbc.m111.262543
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发表时间：
2012-01-27
影响因子：
4.8
通讯作者：
Lasalde-Dominicci, Jose A.
中科院分区：
文献类型：
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作者：
Ballester, Leomar Y.;Capo-Velez, Coral M.;Lasalde-Dominicci, Jose A.
在3000万艾滋病毒感染者中，约有30-50%出现从轻微症状到痴呆的神经系统并发症。HIV不会感染神经元，HIV相关的神经认知衰退背后的分子机制尚不清楚。有几种假说可以解释HIV+个体中痴呆的发展，包括受感染的小胶质细胞介导的神经炎症和HIV蛋白介导的神经元毒性。与HIV神经系统并发症相关的关键蛋白gp120是病毒包膜的一部分，可在感染者的脑脊液中发现。HIV-1-gp120与多种受体相互作用，包括CD4、CCR5、CXCR4和烟碱乙酰胆碱受体（nAChRs）。然而，nachr在hiv相关神经认知障碍中的作用尚未被研究。我们研究了gp120（IIIB）对烟碱受体α 7 （α 7- nachr）表达和功能的影响。我们的研究结果表明，gp120通过激活CXCR4趋化因子受体，诱导α 7-nAChRs的功能性上调。由于α 7-nAChRs对Ca2+具有高通透性，我们通过TUNEL染色来研究受体上调对细胞活力的影响。我们的数据显示细胞死亡增加，这是由选择性拮抗剂α -班加罗毒素阻断。体外数据得到RT-PCR和Western blot分析的支持，证实gp120转基因小鼠脑内α 7-nAChR显著上调。具体来说，在小鼠纹状体中观察到α 7-nAChR的上调，而纹状体在HIV+患者中受到严重影响。综上所述，CXCR4激活诱导α 7-nAChR上调，导致细胞死亡，这表明α 7-nAChR是先前未被认识到的与HIV感染相关的神经毒性的因素。
Approximately 30-50% of the >30 million HIV-infected subjects develop neurological complications ranging from mild symptoms to dementia. HIV does not infect neurons, and the molecular mechanisms behind HIV-associated neurocognitive decline are not understood. There are several hypotheses to explain the development of dementia in HIV+ individuals, including neuroinflammation mediated by infected microglia and neuronal toxicity by HIV proteins. A key protein associated with the neurological complications of HIV, gp120, forms part of the viral envelope and can be found in the CSF of infected individuals. HIV-1-gp120 interacts with several receptors including CD4, CCR5, CXCR4, and nicotinic acetylcholine receptors (nAChRs). However, the role of nAChRs in HIV-associated neurocognitive disorder has not been investigated. We studied the effects of gp120(IIIB) on the expression and function of the nicotinic receptor alpha 7 (alpha 7-nAChR). Our results show that gp120, through activation of the CXCR4 chemokine receptor, induces a functional up-regulation of alpha 7-nAChRs. Because alpha 7-nAChRs have a high permeability to Ca2+, we performed TUNEL staining to investigate the effects of receptor up-regulation on cell viability. Our data revealed an increase in cell death, which was blocked by the selective antagonist alpha-bungarotoxin. The in vitro data are supported by RT-PCR and Western blot analysis, confirming a remarkable up-regulation of the alpha 7-nAChR in gp120-transgenic mice brains. Specifically, alpha 7-nAChR up-regulation is observed in mouse striatum, a region severely affected in HIV+ patients. In summary, CXCR4 activation induces up-regulation of alpha 7-nAChR, causing cell death, suggesting that alpha 7-nAChR is a previously unrecognized contributor to the neurotoxicity associated with HIV infection.