Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity
Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity
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DOI：
10.1038/mt.2008.60
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发表时间：
2008-06-01
影响因子：
12.4
通讯作者：
Kaspar, Brian K.
中科院分区：
文献类型：
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作者：
Dodge, James C.;Haidet, Amanda M.;Kaspar, Brian K.
肌萎缩侧索硬化症（ALS）是一种致命的运动系统神经退行性疾病。最近对啮齿类动物ALS模型的研究表明，胰岛素样生长因子-1 （IGF-1）在疾病发病时释放，可减缓疾病进展。然而，IGF-1在神经肌肉轴上的作用机制尚不清楚。在这项研究中，有症状的ALS小鼠通过立体定向注射表达IGF-1的病毒载体到小脑深部核（DCN）接受IGF-1治疗，DCN是小脑中具有广泛脑干和脊髓连接的区域。我们发现，将IGF-1输送到中枢神经系统（CNS）可减少ALS小鼠的神经病理学，改善肌肉力量，并显着延长ALS小鼠的寿命。为了探索IGF-1的作用机制，我们使用了一种新建立的ALS体外模型。我们证明IGF-1具有强大的神经保护作用，并能减弱神经胶质细胞介导的肿瘤坏死因子- α (tnf - α)和一氧化氮（NO）的释放。我们的研究结果表明，在家族性ALS小鼠模型中，将IGF-1传递到中枢神经系统足以延缓疾病进展，并首次证明IGF-1可以减弱导致疾病进展的非神经元细胞的病理活性。我们的发现强调了一种将IGF-1输送到中枢神经系统的创新方法。
Amyotrophic lateral sclerosis ( ALS) is a fatal neurodegenerative disease of the motor system. Recent work in rodent models of ALS has shown that insulin-like growth factor-1 ( IGF-1) slows disease progression when delivered at disease onset. However, IGF-1's mechanism of action along the neuromuscular axis remains unclear. In this study, symptomatic ALS mice received IGF-1 through stereotaxic injection of an IGF-1-expressing viral vector to the deep cerebellar nuclei ( DCN), a region of the cerebellum with extensive brain stem and spinal cord connections. We found that delivery of IGF-1 to the central nervous system ( CNS) reduced ALS neuropathology, improved muscle strength, and significantly extended life span in ALS mice. To explore the mechanism of action of IGF-1, we used a newly developed in vitro model of ALS. We demonstrate that IGF-1 is potently neuroprotective and attenuates glial cell-mediated release of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide ( NO). Our results show that delivering IGF-1 to the CNS is sufficient to delay disease progression in a mouse model of familial ALS and demonstrate for the first time that IGF-1 attenuates the pathological activity of non-neuronal cells that contribute to disease progression. Our findings highlight an innovative approach for delivering IGF-1 to the CNS.