Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. In the SOD1^G93A mouse model of ALS, abnormal proteins such as misfolded SOD1 and SOD1 oligomers are detected inside and outside of motor neurons. The concept named “glymphatic system” has recently been proposed as a waste clearance mechanism where aquaporin-4 (AQP4) is essential for generating a convective water flow in the brain. Recently we reported the overexpression and mislocalization of AQP4 in SOD1^G93A mice during the disease progression.
First, we investigated whether SOD1 oligomers were cleared by the glymphatic system using AQP4-deficient mice. The clearance of SOD1 oligomers in AQP4-deficient mice was reduced compared to that in WT mice. Next, to evaluate how aberrant AQP4 affect the clearance capacity of SOD1^G93A mice, fluorescently labeled ovalbumin (OVA) was injected into the CSF. The observed OVA clearance was evidently delayed in SOD1^G93A mice compared with WT mice.
These results suggest that the glymphatic system is abnormal and that waste clearance is delayed in SOD1^G93A mice. Since we have also observed OVA uptake by perivascular macrophages (PVM), the innate immune cells residing in the CNS, we will discuss the possible roles of PVM-mediated waste clearance in SOD1^G93A mice.