Abstract
Overexpression and mislocalization of aquaporin-4 (AQP4) in the SOD1G93A 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 SOD1G93A;AQP4−/− mice compared with SOD1G93A 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 SOD1G93A mice compared to wild-type mice. These results suggest that the glymphatic system is abnormal and that waste clearance is delayed in SOD1G93A mice.
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