Overexpression and mislocalization of aquaporin-4 (AQP4) in the SOD1^G93A mouse model of amyotrophic lateral sclerosis (ALS) have previously been reported. However, how alterations of AQP4 affect interstitial bulk flow in the brain and spinal cord, the so-called glymphatic system, is unclear. Here, we report an enhanced accumulation of disease-associated SOD1 species including SOD1 oligomers in SOD1^G93A;AQP4^−/− mice compared with SOD1^G93A mice during ALS disease progression, as analyzed by sandwich ELISA. By directly injecting SOD1 oligomers into the spinal cord parenchyma, we observed a significantly larger delay in clearance of biotinylated or fluorescent-labeled SOD1 oligomers in AQP4^−/− mice than in wild-type mice. Furthermore, when we injected the fluorescent-labeled tracer protein ovalbumin into the cisterna magna and analyzed the tracer distribution in the cervical spinal cord, approximately 35 % processing ability was found to be reduced in SOD1^G93A mice compared to wild-type mice. These results suggest that the glymphatic system is abnormal and that waste clearance is delayed in SOD1^G93A mice.

先前已经报道了肌萎缩侧索硬化症 (ALS)的 SOD1 ^G93A小鼠模型中水通道蛋白 4 (AQP4) 的过度表达和错误定位。然而，AQP4 的改变如何影响大脑和脊髓（即所谓的淋巴系统）中的间质体积流量尚不清楚。在这里，我们报告了疾病相关的 SOD1 种类的增加，包括 SOD1 G93A 中的 SOD1 寡聚体^；通过夹心 ELISA 分析，与 SOD1 G93A 小鼠相比， AQP4 ^-/-小鼠与 SOD1 ^{G93A小鼠相比。}通过将 SOD1 寡聚体直接注射到脊髓实质中，我们观察到 AQP4 中生物素化或荧光标记的 SOD1 寡聚体的清除延迟明显更大^-/-小鼠比野生型小鼠。此外，当我们将荧光标记的示踪蛋白卵清蛋白注入小脑池并分析颈脊髓中示踪剂的分布时，发现与野生型小鼠相比，SOD1 ^{G93A小鼠的处理能力降低了约 35%。}这些结果表明，在 SOD1 ^G93A小鼠中，glymphatic 系统异常并且废物清除延迟。