Stagnation of glymphatic interstitial fluid flow and delay in waste clearance in the SOD1-G93A mouse model of ALS

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. (C) 2020 The Author(s). Published by Elsevier B.V.

Automated summary

The study indicates that abnormal expression and mislocalization of AQP4 in SOD1(G93A) mice result in dysfunction of the glymphatic system, leading to delayed waste clearance and exacerbation of ALS disease progression.