Apelin deficiency accelerates the progression of amyotrophic lateral sclerosis.
Apelin deficiency accelerates the progression of amyotrophic lateral sclerosis.
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Apelin缺乏加速了肌萎缩性侧索硬化症的进展。
DOI：
10.1371/journal.pone.0023968
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Maeda S
中科院分区：
文献类型：
--
作者：
Kasai A;Kinjo T;Ishihara R;Sakai I;Ishimaru Y;Yoshioka Y;Yamamuro A;Ishige K;Ito Y;Maeda S
肌萎缩侧索硬化症(ALS)是一种以运动神经元选择性丢失为特征的神经退行性疾病。最近的研究表明，慢性缺氧和血管内皮生长因子(VEGF)依赖的神经保护不足可能导致ALS运动神经元的变性。Apelin是G蛋白偶联受体APJ的内源性配体，其表达受低氧调节。此外，最近的报道表明，apelin可以保护神经元免受谷氨酸诱导的兴奋性毒性。在这里，我们使用ALS的SOD1G93A小鼠模型检验了apelin是否是一种内源性神经保护因子。在小鼠中枢神经系统组织中，apelin和APJ的mRNAs在脊髓中表达最高。APJ免疫反应阳性神经元胞体位于脊髓灰质。虽然4~18周龄野生型小鼠脊髓中apelin mRNA的表达没有变化，但SOD1G93A小鼠的脊髓apelin mRNA表达随着瘫痪表型的增加而降低。此外，双突变体APELIN缺陷型和SOD1G93A的发病表型早于SOD1G93A。免疫组织化学观察显示，双突变小鼠脊髓运动神经元数量减少，小胶质细胞激活，提示apelin缺乏在病理上加速了ALS的进展。此外，我们还发现apelin增强了血管内皮细胞生长因子对过氧化氢诱导的原代神经元死亡的保护作用。这些结果提示脊髓内的APELIN/APJ系统对ALS的发病具有神经保护作用。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Recent studies have implicated that chronic hypoxia and insufficient vascular endothelial growth factor (VEGF)-dependent neuroprotection may lead to the degeneration of motor neurons in ALS. Expression of apelin, an endogenous ligand for the G protein-coupled receptor APJ, is regulated by hypoxia. In addition, recent reports suggest that apelin protects neurons against glutamate-induced excitotoxicity. Here, we examined whether apelin is an endogenous neuroprotective factor using SOD1G93A mouse model of ALS. In mouse CNS tissues, the highest expressions of both apelin and APJ mRNAs were detected in spinal cord. APJ immunoreactivity was observed in neuronal cell bodies located in gray matter of spinal cord. Although apelin mRNA expression in the spinal cord of wild-type mice was not changed from 4 to 18 weeks age, that of SOD1G93A mice was reduced along with the paralytic phenotype. In addition, double mutant apelin-deficient and SOD1G93A displayed the disease phenotypes earlier than SOD1G93A littermates. Immunohistochemical observation revealed that the number of motor neurons was decreased and microglia were activated in the spinal cord of the double mutant mice, indicating that apelin deficiency pathologically accelerated the progression of ALS. Furthermore, we showed that apelin enhanced the protective effect of VEGF on H2O2-induced neuronal death in primary neurons. These results suggest that apelin/APJ system in the spinal cord has a neuroprotective effect against the pathogenesis of ALS.
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