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

Mikako Hirose; Mito Asano; Saori Watanabe-Matsumoto; Koji Yamanaka; Yoichiro Abe; Masato Yasui; Eiichi Tokuda; Yoshiaki Furukawa; Hidemi Misawa

doi:10.1016/j.neures.2020.10.006

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

Mikako Hirose, Mito Asano, Saori Watanabe-Matsumoto, Koji Yamanaka, Yoichiro Abe, Masato Yasui, Eiichi Tokuda, Yoshiaki Furukawa, Hidemi Misawa

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	74-82
Number of pages	9
Journal	Neuroscience Research
Volume	171
DOIs	https://doi.org/10.1016/j.neures.2020.10.006
Publication status	Published - Oct 2021
Externally published	Yes

Keywords

ALS
AQP4
Glymphatic system
Misfolded SOD1
SOD1 oligomers
Spinal cord

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10.1016/j.neures.2020.10.006

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

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.",

keywords = "ALS, AQP4, Glymphatic system, Misfolded SOD1, SOD1 oligomers, Spinal cord",

author = "Mikako Hirose and Mito Asano and Saori Watanabe-Matsumoto and Koji Yamanaka and Yoichiro Abe and Masato Yasui and Eiichi Tokuda and Yoshiaki Furukawa and Hidemi Misawa",

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year = "2021",

month = oct,

doi = "10.1016/j.neures.2020.10.006",

language = "English",

volume = "171",

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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

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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ER -

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

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