School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.
Queensland Brain Institute, the University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.
Mol Neurobiol. 2020 Oct;57(10):4143-4155. doi: 10.1007/s12035-020-02019-9. Epub 2020 Jul 16.
Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron degenerative disease that is without effective treatment. The receptor for advanced glycation end products (RAGE) is a major component of the innate immune system that has been implicated in ALS pathogenesis. However, the contribution of RAGE signalling to the neuroinflammation that underlies ALS neurodegeneration remains unknown. The present study therefore generated SOD1 mice lacking RAGE and compared them with SOD1 transgenic ALS mice in respect to disease progression (i.e. body weight, survival and muscle strength), neuroinflammation and denervation markers in the spinal cord and tibialis anterior muscle. We found that complete absence of RAGE signalling exerted a protective effect on SOD1 pathology, slowing disease progression and significantly extending survival by ~ 3 weeks and improving motor function (rotarod and grip strength). This was associated with reduced microgliosis, cytokines, innate immune factors (complement, TLRs, inflammasomes), and oxidative stress in the spinal cord, and a reduction of denervation markers in the tibialis anterior muscle. We also documented that RAGE mRNA expression was significantly increased in the spinal cord and muscles of preclinical SOD1 and TDP43 models of ALS, supporting a widespread involvement for RAGE in ALS pathology. In summary, our results indicate that RAGE signalling drives neuroinflammation and contributes to neurodegeneration in ALS and highlights RAGE as a potential immune therapeutic target for ALS.
肌萎缩侧索硬化症（ALS）是一种致命且迅速进展的运动神经元退行性疾病，目前尚无有效治疗方法。晚期糖基化终产物受体（RAGE）是先天免疫系统的主要组成部分，与 ALS 的发病机制有关。然而，RAGE 信号对 ALS 神经退行性变所涉及的神经炎症的贡献尚不清楚。因此，本研究生成了缺乏 RAGE 的 SOD1 小鼠，并将其与 SOD1 转基因 ALS 小鼠进行了比较，以评估疾病进展（即体重、存活和肌肉力量）、脊髓和比目鱼肌中的神经炎症和去神经标记物。我们发现，完全缺乏 RAGE 信号对 SOD1 病理学具有保护作用，可减缓疾病进展，并使存活时间显著延长约 3 周，改善运动功能（转棒和握力）。这与脊髓中的小胶质细胞增生、细胞因子、先天免疫因子（补体、TLR、炎性体）和氧化应激减少以及比目鱼肌去神经标记物减少有关。我们还记录到，RAGE mRNA 表达在 ALS 的 SOD1 和 TDP43 前临床模型的脊髓和肌肉中显著增加，这支持了 RAGE 在 ALS 病理学中的广泛参与。总之，我们的结果表明，RAGE 信号驱动神经炎症并导致 ALS 中的神经退行性变，并强调 RAGE 是 ALS 的潜在免疫治疗靶点。
