Neuroprotective effect of activity-dependent neurotrophic factor against toxicity from familial amyotrophic lateral sclerosis-linked mutant SOD1 in vitro and in vivo
Neuroprotective effect of activity-dependent neurotrophic factor against toxicity from familial amyotrophic lateral sclerosis-linked mutant SOD1 in vitro and in vivo
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DOI：
10.1002/jnr.20305
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发表时间：
2004-11-15
影响因子：
4.2
通讯作者：
Nishimoto, I
中科院分区：
文献类型：
--
作者：
Chiba, T;Hashimoto, Y;Nishimoto, I
肌萎缩性侧索硬化症（ALS）是最常见的致死性运动神经元疾病，主要影响中年人。目前还没有治愈ALS的方法。一些证据支持家族性ALS （FALS）相关突变体Cu/Zn -超氧化物歧化酶-1 （SOD1）基因的促凋亡特性可能在一些FALS病例的发病机制中发挥重要作用。在这里，我们发现活动依赖性神经营养因子（ADNF），一种最初被鉴定为具有抗阿尔茨海默病（AD）活性的神经营养因子，以剂量反应的方式保护由fals相关的A4T-， G85R-和G93R-SOD1引起的神经元细胞死亡。值得注意的是，在低至100 fM的浓度下，adnf介导的SOD1突变体诱导的神经元细胞死亡的完全抑制发生。即使浓度超过1nm， ADNF仍能保持神经保护活性。这与之前的研究结果形成鲜明对比，即当浓度超过1 nM时，ADNF失去了对AD相关损伤（包括一些家族性AD基因和淀粉样蛋白-肽）诱导的神经毒性的保护活性。ADNF对SOD1突变引起的细胞死亡的神经保护活性的表征表明，CaMKIV和某些酪氨酸激酶参与了ADNF介导的神经保护。此外，体内研究表明，脑室内给予ADNF可显著改善G93A-SOD1转基因小鼠（FALS的一种广泛使用的模型）的运动表现，尽管生存期仅略微延长。因此，ADNF的神经保护活性为ALS治疗药物的开发提供了新的见解。(C) 2004 Wiley-Liss, Inc。
Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease, affecting mostly middle-aged people. There are no curative therapies for ALS. Several lines of evidence have supported the notion that the proapoptotic property of familial ALS (FALS)-linked mutant Cu/Zn -superoxide dismutase-1 (SOD1) genes may play an important role in the pathogenesis of some FALS cases. Here we found that activity-dependent neurotrophic factor (ADNF), a neurotrophic factor originally identified to have the anti-Alzheimer's disease (AD) activity, protected against neuronal cell death caused by FALS-linked A4T-, G85R- and G93R-SOD1 in a dose-responsive fashion. Notably, ADNF-mediated complete suppression of SOD1 mutant-induced neuronal cell death occurs at concentrations as low as 100 fM. ADNF maintains the neuroprotective activity even at concentrations of more than 1 nM. This is in clear contrast to the previous finding that ADNF loses its protective activity against neurotoxicity induced by AD-relevant insults, including some familial AD genes and amyloid beta peptide at concentrations of more than 1 nM. Characterization of the neuroprotective activity of ADNF against cell death caused by SOD1 mutants revealed that CaMKIV and certain tyrosine kinases are involved in ADNF-mediated neuroprotection. Moreover, in vivo studies showed that intracerebroventricularly administered ADNF significantly improved motor performance of G93A-SOD1 transgenic mice, a widely used model of FALS, although survival was extended only marginally. Thus, the neuroprotective activity of ADNF provides a novel insight into the development of curative drugs for ALS. (C) 2004 Wiley-Liss, Inc.