TY - JOUR
T1 - Stagnation of glymphatic interstitial fluid flow and delay in waste clearance in the SOD1-G93A mouse model of ALS
AU - Hirose, Mikako
AU - Asano, Mito
AU - Watanabe-Matsumoto, Saori
AU - Yamanaka, Koji
AU - Abe, Yoichiro
AU - Yasui, Masato
AU - Tokuda, Eiichi
AU - Furukawa, Yoshiaki
AU - Misawa, Hidemi
N1 - Funding Information:
This work was supported by a JSPS KAKENHI Grant Number 19K07128 (to H.M.), and by a Grant-in-Aid for Program for the Advancement of Next Generation Research Projects from Keio University (to Y.F., M.Y., H.M.).
Publisher Copyright:
© 2020 The Author(s)
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
KW - ALS
KW - AQP4
KW - Glymphatic system
KW - Misfolded SOD1
KW - SOD1 oligomers
KW - Spinal cord
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U2 - 10.1016/j.neures.2020.10.006
DO - 10.1016/j.neures.2020.10.006
M3 - Article
C2 - 33316302
AN - SCOPUS:85098667101
SN - 0168-0102
VL - 171
SP - 74
EP - 82
JO - Neuroscience Research
JF - Neuroscience Research
ER -