Caspase cascades in human immunodeficiency virus-associated neurodegeneration
Caspase cascades in human immunodeficiency virus-associated neurodegeneration
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DOI：
10.1523/jneurosci.22-10-04015.2002
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发表时间：
2002-05-15
影响因子：
5.3
通讯作者：
Lipton, SA
中科院分区：
文献类型：
--
作者：
Garden, GA;Budd, SL;Lipton, SA
许多感染人类免疫缺陷病毒-1（HIV-1）的患者会出现一种神经功能恶化综合征，称为HIV相关性痴呆（HAD）。神经元没有被HIV-1感染，因此，HIV诱导的神经元损伤的机制仍然不完全清楚。一些研究者已经观察到神经元损伤的证据，包括树突状细胞变性，以及HAD患者CNS组织中的细胞凋亡。半胱天冬酶，与细胞凋亡过程相关的蛋白酶，作为无活性的酶原合成，并在暴露于细胞凋亡信号后在蛋白水解级联中被激活。在这里，我们证明，HAD与活跃的caspase-3样免疫反应性，是本地化的索马和树突的神经元在受影响的地区的人的大脑。此外，使用HIV诱导的神经元凋亡的体外模型研究了半胱天冬酶激活的级联反应。在暴露于HIV外壳蛋白gp 120的皮层培养物中观察到caspase-3蛋白水解活性增加和细胞色素c的线粒体释放。Fas/肿瘤坏死因子-α/死亡受体途径和线粒体半胱天冬酶途径的特异性抑制剂阻止了gp 120诱导的神经元凋亡。半胱天冬酶抑制还防止了在CNS表达HIV/gp 120的转基因小鼠中体内观察到的树突变性。这些发现表明，针对半胱天冬酶途径的药物干预可能有利于预防或治疗HAD。
Many patients infected with human immunodeficiency virus-1 (HIV-1) develop a syndrome of neurologic deterioration known as HIV-associated dementia (HAD). Neurons are not productively infected by HIV-1; thus, the mechanism of HIV-induced neuronal injury remains incompletely understood. Several investigators have observed evidence of neuronal injury, including dendritic degeneration, and apoptosis in CNS tissue from patients with HAD. Caspase enzymes, proteases associated with the process of apoptosis, are synthesized as inactive proenzymes and are activated in a proteolytic cascade after exposure to apoptotic signals. Here we demonstrate that HAD is associated with active caspase-3-like immunoreactivity that is localized to the soma and dendrites of neurons in affected regions of the human brain. Additionally, the cascade of caspase activation was studied using an in vitro model of HIV-induced neuronal apoptosis. Increased caspase-3 proteolytic activity and mitochondrial release of cytochrome c were observed in cerebrocortical cultures exposed to the HIV coat protein gp120. Specific inhibitors of both the Fas/tumor necrosis factor-alpha/death receptor pathway and the mitochondrial caspase pathway prevented gp120-induced neuronal apoptosis. Caspase inhibition also prevented the dendrite degeneration observed in vivo in transgenic mice with CNS expression of HIV/gp120. These findings suggest that pharmacologic interventions aimed at the caspase enzyme pathways may be beneficial for the prevention or treatment of HAD.