Brain-derived neurotrophic factor is neuroprotective against human immunodeficiency virus-1 envelope proteins
Brain-derived neurotrophic factor is neuroprotective against human immunodeficiency virus-1 envelope proteins
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DOI：
10.1196/annals.1344.022
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发表时间：
2005-01-01
期刊：
影响因子：
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通讯作者：
Mocchetti, I
中科院分区：
文献类型：
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作者：
Bachis, A;Mocchetti, I
人类免疫缺陷病毒 1 型 (HIV-1) 阳性患者在感染后期会出现艾滋病痴呆综合症，这是一系列神经系统并发症，包括锥体外系症状、认知障碍和精神障碍。这些患者的大脑表现出脑损伤。 HIV-1 包膜糖蛋白 120 (gp120) 被认为是神经元损失的致病因素；然而，感染期间存在多种 gp120 菌株，并且每种菌株的相对神经毒性潜力目前尚不清楚。使用培养的小脑颗粒神经元，我们确定了分别与 CXCR4 和 CCR5 趋化因子受体结合的两种 gp120、gp120IIIB 和 gp120BaL 菌株是否诱导细胞死亡。在暴露于低纳摩尔浓度的 gp120IIIB 或 gp120BaL 的神经元中，细胞凋亡和 caspase-3 激活在几个小时内就很明显。然而，gp120IIIB 的神经毒性作用比 gp120BaL 更快且浓度更低，表明小脑颗粒细胞可能对 CXCR4 受体激活的凋亡信号更敏感。神经营养蛋白脑源性神经营养因子（BDNF）已被证明可以阻止神经元凋亡。因此，我们检查了 BDNF 是否可以抵抗 gp120 的两种菌株。在 gp120 之前将小脑颗粒细胞预先暴露于 BDNF 可减少细胞凋亡，从而提高其存活率。这些发现为探索 BDNF 减少体内 HIV-1 介导的神经元细胞死亡的能力奠定了基础。
Human immunodeficiency virus type 1 (HIV-1)-positive patients in the late phase of infection develop AIDS dementia complex, an array of neurological complications that include extrapyramidal symptoms, cognitive impairments, and psychiatric disturbances. Brains of these patients exhibit brain injury. The HIV-1 envelope glycoprotein 120 (gp120) has been suggested to be a causal agent of neuronal loss; however, several strains of gp120 exist during the infection and the relative neurotoxic potential of each strain is presently unknown. Using cultured cerebellar granule neurons, we determined whether two strains of gp120, gp120IIIB and gp120BaL, which bind to CXCR4 and CCR5 chemokine receptors, respectively, induce cell death. Apoptotic cell death and activated caspase-3 were evident within a few hours in neurons exposed to low nanomolar concentrations of either gp120IIIB or gp120BaL. However, the neurotoxic effect of gp120IIIB was more rapid and occurred at lower concentrations than that of gp120BaL, suggesting that cerebellar granule cells may be more sensitive to apoptotic signals activated by the CXCR4 receptor. The neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to block neuronal apoptosis. Therefore, we examined whether BDNF protects against both strains of gp120. Preexposure of cerebellar granule cells to BDNF prior to both gp120s decreased apoptosis and consequently enhanced their survival. These findings underlie the rationale for exploring the ability of BDNF to reduce HIV-1-mediated neuronal cell death in vivo.