Effects of RAGE inhibition on the progression of the disease in hSOD1G93A ALS mice.
Effects of RAGE inhibition on the progression of the disease in hSOD1G93A ALS mice.
复制标题
RAGE 抑制对 hSOD1G93A ALS 小鼠疾病进展的影响。
DOI：
10.1002/prp2.636
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发表时间：
2020
影响因子：
2.6
通讯作者：
Pehar,Mariana
中科院分区：
文献类型：
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作者：
Liu,Liping;Killoy,KelbyM;Vargas,MarceloR;Yamamoto,Yasuhiko;Pehar,Mariana
星形胶质细胞通过主动诱导运动神经元变性在肌萎缩侧索硬化症（ALS）的进展中起关键作用。从晚期糖基化终末产物受体（receptor for advanced glycation end products，ALS）基因敲除小鼠中分离的运动神经元对ALS星形胶质细胞产生的神经毒性信号具有抗性。在这里，我们证实了在共培养模型中，通过添加抑制剂FPS-ZM 1或RAP来防止由过表达ALS连锁突变体hSOD 1G 93 A的星形胶质细胞诱导的神经元死亡。这些抑制剂还防止了由来自症状性hSOD 1G 93 Amice的脊髓提取物诱导的运动神经元死亡。为了评估这种神经毒性机制在ALS病理学中的相关性，我们评估了FPS-ZM 1在hSOD 1G 93 Amice中的治疗潜力。FPS-ZM 1治疗显著改善了疾病进展期间hSOD 1G 93 Amice的后肢握力，减少了腓肠肌中萎缩标志物的表达，改善了大运动神经元的存活，并减少了脊髓腹角中的神经胶质增生。然而，我们没有观察到该药物在症状发作和hSOD 1G 93 Amice的存活中的统计学显著作用。在具有单倍性不足的hSOD 1G 93 Amice [hSOD 1G 93 A; β（+/-）]中也观察到后肢握力的维持，进一步支持β抑制对肌肉功能的有益作用。然而，完全消融后未观察到任何受益。此外，基因敲除显著缩短了hSOD 1G 93 Amice的中位生存期。这些结果表明，ALS中靶向肌萎缩侧索硬化症的新疗法的进展需要更好地了解其在细胞类型/组织特异性背景下的生理作用。
Astrocytes play a key role in the progression of amyotrophic lateral sclerosis (ALS) by actively inducing the degeneration of motor neurons. Motor neurons isolated from receptor for advanced glycation end products (RAGE)‐knockout mice are resistant to the neurotoxic signal derived from ALS‐astrocytes. Here, we confirmed that in a co‐culture model, the neuronal death induced by astrocytes over‐expressing the ALS‐linked mutant hSOD1G93Ais prevented by the addition of the RAGE inhibitors FPS‐ZM1 or RAP. These inhibitors also prevented the motor neuron death induced by spinal cord extracts from symptomatic hSOD1G93Amice. To evaluate the relevance of this neurotoxic mechanism in ALS pathology, we assessed the therapeutic potential of FPS‐ZM1 in hSOD1G93Amice. FPS‐ZM1 treatment significantly improved hind‐limb grip strength in hSOD1G93Amice during the progression of the disease, reduced the expression of atrophy markers in the gastrocnemius muscle, improved the survival of large motor neurons, and reduced gliosis in the ventral horn of the spinal cord. However, we did not observe a statistically significant effect of the drug in symptoms onset nor in the survival of hSOD1G93Amice. Maintenance of hind‐limb grip strength was also observed in hSOD1G93Amice with RAGE haploinsufficiency [hSOD1G93A;RAGE(+/‐)], further supporting the beneficial effect of RAGE inhibition on muscle function. However, no benefits were observed after complete RAGE ablation. Moreover, genetic RAGE ablation significantly shortened the median survival of hSOD1G93Amice. These results indicate that the advance of new therapies targeting RAGE in ALS demands a better understanding of its physiological role in a cell type/tissue‐specific context.