肌萎缩侧索硬化 (ALS)是一种以脑和脊髓运动神经元的进行性退化为特征的致死性神经退行性疾病。该疾病至今尚无针对病因的有效治疗方法。研究认为，ALS是一种淀粉样蛋白疾病，突变的Cu/Zn超氧化物歧化酶（SOD1）病理性聚集成毒性寡聚物并沉积在运动神经元中是ALS发病的主要诱因之一。业已证明，多种具有不同一级序列的淀粉样蛋白聚集后能够形成具有相似的结构特征和细胞毒性机理的寡聚物，因此，特异靶向淀粉样蛋白寡聚体所共有结构特征的制剂将成为治疗ALS的理想策略。基于此，本论文应用寡聚体特异性抗体W20对SOD1-G93A转基因小鼠进行了治疗研究。ALS还表现出神经炎症和胶质细胞过度活化等重要的病理特征。SOD1的异常聚集和沉积导致胶质细胞过度激活，进而促进了IL-1β等炎症因子的大量释放，诱导神经元的功能紊乱和凋亡，并进一步刺激胶质细胞对IL-1β的产生和释放，并放大了神经炎症状态。因此阻断IL-1β成为治疗ALS的有前景的手段之一。本论文应用特异靶向IL-1β的表位疫苗A1β，探究其对于SOD1-G93A转基因小鼠的治疗作用。我们的研究结果表明，两种免疫策略都能够显著提高SOD1-G93A小鼠的运动机能，改善小鼠运动神经元的性活，抑制神经元的凋亡，并有效降低小鼠脊髓和脑干中SOD1的沉积和毒性SOD1寡聚体水平，抑制胶质细胞的过度活化和神经炎症状态。本论文首次揭示了寡聚体特异性抗体以及IL-1β表位疫苗对于ALS均具有较好的治疗潜力，为ALS的治疗提供了新的途径;Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by motor neuron loss in the brain and spinal cord. Mutations in Cu-Zn superoxide dismutase-1 (SOD1) are the first identified genetic mutations that are causative for familial ALS. Soluble SOD1 oligomers are considered the most toxic species and play a key role in the pathologic process of ALS. Here we present a therapeutic strategy for ALS treatment with an oligomer-specific antibody (W20) targeting toxic SOD1 oligomers.Neuroinflammation plays a key role in the pathogenesis of ALS, which is characterized by extensive gliosis and increased level of inflammatory cytokines including IL-1β, IL-6 and TNF-α. Blockade of the key proinflammatory cytokine IL-1β may repesented as a promising therapeutic strategy for the treatment of ALS. In this study, we developed an IL-1β-targeted therapeutic vaccine consisting of an IL-1β epitope peptide (A1β) and assessed its efficacy on a SOD1-G93A mouse model of ALS.Our study showed that both W20 and A1β significantly improved motor neuron survival and motor performance, reduced SOD1 oligomer levels, inhibited gliosis and neuroinflammation in the spinal cords and brain stems of SOD1-G93A mice. These findings for the first time suggest that oligomer-specific antibody W20 and IL-1β-targeted vaccine A1β has promising therapeutic potential for ALS and open a new way for ALS treatment.