Abe, Yoichiro

写真a

Affiliation

School of Medicine, Department of Pharmacology (Shinanomachi)

Position

Research Associate/Assistant Professor/Instructor

External Links
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Career 【 Display / hide 】

  • 1997.04
    -
    1999.03

    Institute of Basic Medical Sciences, University of Tsukuba, Department of Pharmacology, Research Associate

  • 1999.04
    -
    2007.03

    School of Medicine, Keio University, Department of Pharmacology, Instructor

  • 2007.04
    -
    2009.03

    School of Medicine, Keio University, Department of Pharmacology, Instructor

  • 2009.04
    -
    Present

    School of Medicine, Keio University, Department of Pharmacology, associate professor

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Academic Degrees 【 Display / hide 】

  • 博士（医学）, University of Tsukuba, Coursework

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Research Areas 【 Display / hide 】

  • Life Science / Molecular biology

  • Life Science / Pharmacology

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Research Keywords 【 Display / hide 】

  • aquaporin-4

  • astrocyte

  • neurodegenerative dieseases

  • neuromyelitis optica

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Papers 【 Display / hide 】

  • Humanized-Aquaporin-4-Expressing Rat Created by Gene-Editing Technology and Its Use to Clarify the Pathology of Neuromyelitis Optica Spectrum Disorder

    Namatame C., Abe Y., Miyasaka Y., Takai Y., Matsumoto Y., Takahashi T., Mashimo T., Misu T., Fujihara K., Yasui M., Aoki M.

    International Journal of Molecular Sciences 25 ( 15 )  2024.08

    ISSN  16616596

    　View Summary

    Conventional rodent neuromyelitis optica spectrum disorder (NMOSD) models using patient-derived immunoglobulin G (IgG) are potentially affected by the differences between the human and rodent aquaporin-4 (AQP4) extracellular domains (ECDs). We hypothesized that the humanization of AQP4 ECDs would make the rodent model lesions closer to human NMOSD pathology. Humanized-AQP4-expressing (hAQP4) rats were generated using genome-editing technology, and the human AQP4-specific monoclonal antibody (mAb) or six patient-derived IgGs were introduced intraperitoneally into hAQP4 rats and wild-type Lewis (WT) rats after immunization with myelin basic protein and complete Freund’s adjuvant. Human AQP4-specific mAb induced astrocyte loss lesions specifically in hAQP4 rats. The patient-derived IgGs also induced NMOSD-like tissue-destructive lesions with AQP4 loss, demyelination, axonal swelling, complement deposition, and marked neutrophil and macrophage/microglia infiltration in hAQP4 rats; however, the difference in AQP4 loss lesion size and infiltrating cells was not significant between hAQP4 and WT rats. The patient-derived IgGs bound to both human and rat AQP4 M23, suggesting their binding to the shared region of human and rat AQP4 ECDs. Anti-AQP4 titers positively correlated with AQP4 loss lesion size and neutrophil and macrophage/microglia infiltration. Considering that patient-derived IgGs vary in binding sites and affinities and some of them may not bind to rodent AQP4, our hAQP4 rat is expected to reproduce NMOSD-like pathology more accurately than WT rats.

  • A tyrosine-based YXXΦ motif regulates the degradation of aquaporin-4 via both lysosomal and proteasomal pathways and is functionally inhibited by a 10-amino-acid sequence within its C-terminus

    Wang Y., Suzuki R., Fujii A., Ieki K., Goda W., Yasui M., Abe Y.

    FEBS Journal (FEBS Journal)  290 ( 10 ) 2616 - 2635 2023

    ISSN  1742464X

    　View Summary

    Aquaporin-4 (AQP4) is a dominant water channel in the brain and is expressed on astrocytic end-feet, mediating water homeostasis in the brain. AQP4 is a target of an inflammatory autoimmune disease, neuromyelitis optica spectrum disorders (NMOSD), that causes demyelination. An autoantibody recognizing the extracellular domains of AQP4, called NMO-IgG, is critically implicated in the pathogenesis of the disease. Complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in astrocytes are the primary causes of the disease, preceding demyelination and neuronal damage. Additionally, some cytotoxic effects of binding of NMO-IgG to AQP4, independent of CDC/ADCC, have been proposed. Antibody-induced endocytosis of AQP4 is thought to be involved in CDC/ADCC-independent cytotoxicity induced by the binding of NMO-IgG to AQP4. To clarify the mechanism responsible for antibody-induced endocytosis of AQP4, we investigated the subcellular localization and trafficking of AQP4, focusing on its C-terminal domain, by making a variety of deletion and substitution mutants of mouse AQP4. We found that a tyrosine-based YXXΦ motif in the C-terminal domain of AQP4 plays a critical role in the steady-state subcellular localization/turnover and antibody-induced endocytosis/lysosomal degradation of AQP4. Our results indicate that the YXXΦ motif has to escape the inhibitory effect of the C-terminal 10-amino-acid sequence and be located at an appropriate distance from the plasma membrane to act as a signal for lysosomal degradation of AQP4. In addition to lysosomal degradation, we demonstrated that the YXXΦ motif also functions as a signal to degrade AQP4 using proteasomes under specific conditions.

  • Aquaporin-4 in Neuromyelitis Optica Spectrum Disorders: A Target of Autoimmunity in the Central Nervous System

    Abe Y., Yasui M.

    Biomolecules (Biomolecules)  12 ( 4 )  2022.04

    　View Summary

    Since the discovery of a specific autoantibody in patients with neuromyelitis optica spectrum disorder (NMOSD) in 2004, the water channel aquaporin-4 (AQP4) has attracted attention as a target of autoimmune diseases of the central nervous system. In NMOSD, the autoantibody (NMO-IgG) binds to the extracellular loops of AQP4 as expressed in perivascular astrocytic end-feet and disrupts astrocytes in a complement-dependent manner. NMO-IgG is an excellent marker for distinguishing the disease from other inflammatory demyelinating diseases, such as multiple sclerosis. The unique higher-order structure of AQP4—called orthogonal arrays of particles (OAPs)—as well as its subcellular localization may play a crucial role in the pathogenesis of the disease. Recent studies have also demonstrated complement-independent cytotoxic effects of NMO-IgG. Antibody-induced endocytosis of AQP4 has been suggested to be involved in this mechanism. This review focuses on the binding properties of antibodies that recognize the extracellular region of AQP4 and the characteristics of AQP4 that are implicated in the pathogenesis of NMOSD.

  • Quantitative measurement of diffusion-weighted imaging signal using expression-controlled aquaporin-4 cells: Comparative study of 2-compartment and diffusion kurtosis imaging models

    Imaizumi A., Obata T., Kershaw J., Tachibana Y., Abe Y., Shibata S., Nitta N., Aoki I., Yasui M., Higashi T.

    PLoS ONE (PLoS ONE)  17 ( 4 April )  2022.04

    ISSN  1932-6203

    　View Summary

    The purpose of this study was to compare parameter estimates for the 2-compartment and diffusion kurtosis imaging models obtained from diffusion-weighted imaging (DWI) of aquaporin-4 (AQP4) expression-controlled cells, and to look for biomarkers that indicate differences in the cell membrane water permeability. DWI was performed on AQP4-expressing and non-expressing cells and the signal was analyzed with the 2-compartment and diffusion kurtosis imaging models. For the 2-compartment model, the diffusion coefficients (Df, Ds) and volume fractions (Ff, Fs, Ff = 1-Fs) of the fast and slow compartments were estimated. For the diffusion kurtosis imaging model, estimates of the diffusion kurtosis (K) and corrected diffusion coefficient (D) were obtained. For the 2-compartment model, Ds and Fs showed clear differences between AQP4-expressing and non-expressing cells. Fs was also sensitive to cell density. There was no clear relationship with the cell type for the diffusion kurtosis imaging model parameters. Changes to cell membrane water permeability due to AQP4 expression affected DWI of cell suspensions. For the 2-compartment and diffusion kurtosis imaging models, Ds was the parameter most sensitive to differences in AQP4 expression.

  • Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration

    Ishida K., Yamada K., Nishiyama R., Hashimoto T., Nishida I., Abe Y., Yasui M., Iwatsubo T.

    Journal of Experimental Medicine (Journal of Experimental Medicine)  219 ( 3 )  2022.03

    ISSN  00221007

    　View Summary

    Accumulation of tau has been implicated in various neurodegenerative diseases termed tauopathies. Tau is a microtubule-associated protein but is also actively released into the extracellular fluids including brain interstitial fluid and cerebrospinal fluid (CSF). However, it remains elusive whether clearance of extracellular tau impacts tau-associated neurodegeneration. Here, we show that aquaporin-4 (AQP4), a major driver of the glymphatic clearance system, facilitates the elimination of extracellular tau from the brain to CSF and subsequently to deep cervical lymph nodes. Strikingly, deletion of AQP4 not only elevated tau in CSF but also markedly exacerbated phosphorylated tau deposition and the associated neurodegeneration in the brains of transgenic mice expressing P301S mutant tau. The current study identified the clearance pathway of extracellular tau in the central nervous system, suggesting that glymphatic clearance of extracellular tau is a novel regulatory mechanism whose impairment contributes to tau aggregation and neurodegeneration.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Prolonged Light Exposure Induces Circadian Impairment in Aquaporin-4-Knockout Mice

    Murakami A., Tsuji K., Isoda M., Matsuo M., Abe Y., Yasui M., Okamura H., Tominaga K.

    Journal of Biological Rhythms (Journal of Biological Rhythms)  38 ( 2 ) 208 - 214 2023

    ISSN  07487304

    　View Summary

    Astrocytes are densely present in the suprachiasmatic nucleus (SCN), which is the master circadian oscillator in mammals, and are presumed to play a key role in circadian oscillation. However, specific astrocytic molecules that regulate the circadian clock are not yet well understood. In our study, we found that the water channel aquaporin-4 (AQP4) was abundantly expressed in SCN astrocytes, and we further examined its circadian role using AQP4-knockout mice. There was no prominent difference in circadian behavioral rhythms between Aqp4-/- and Aqp4+/+ mice subjected to light-dark cycles and constant dark conditions. However, exposure to constant light induced a greater decrease in the Aqp4-/- mice rhythmicity. Although the damped rhythm in long-term constant light recovered after transfer to constant dark conditions in both genotypes, the period until the reappearance of original rhythmicity was severely prolonged in Aqp4-/- mice. In conclusion, AQP4 absence exacerbates the prolonged light-induced impairment of circadian oscillations and delays their recovery to normal rhythmicity.

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Presentations 【 Display / hide 】

  • Development of a new Neuromyelitis Optica model mice.

    Chau SH, Abe Y, Yasui M

    The 18th World Congress of Basic and Clinical Pharmacology/The 91st Annual Meeting of the Japanese Pharmacological Society (Kyoto) , 

    2018.07
    , 

    Poster presentation, 日本薬理学会

  • Roles of the C-terminal domain in intracellular trafficking and degradation of AQP4.

    Abe Y, Fujii A, Goda W, and Yasui M

    The 40th Annual Meeting of the Molecular Biology Society of Japan (Kobe) , 

    2017.12
    , 

    Poster presentation

  • Aquaporin-4 is not involved in chronic neuroinflammatory responses in 5xFAD mice.

    Abe Y, Chau S, Wada H, Yasui M, and Niikura T

    The 90th Annual Meeting of the Japanese Pharmacological Society (Nagasaki) , 

    2017.03
    , 

    Poster presentation

  • Glial responses to amyloid β accumulation in aquaporin-4-deficient Alzheimer’s disease model.

    Abe, Y., Chau, S., Wada, H., Yasui, M., and Niikura, T.

    The 39th Annual Meeting of the Japan Neuroscience Society (Yokohama) , 

    2016.07
    , 

    Poster presentation

  • High avidity chimeric monoclonal antibodies against the extracellular domains of human aquaporin-4 competing with NMO-IgG.

    Miyazaki-Komine, K, Abe, Y., Huang, P., Takai, Y., Kusano-Arai, O., Iwanari, H., Misu, T., Sakihama, T., Toyama, Y., Fujihara, K., Hamakubo, T., and Yasui, M.

    The 88th Annual Meeting of the Japanese Pharmacological Society (Nagoya) , 

    2015.03
    , 

    Poster presentation

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • アクアポリン４機能と脳リンパ排泄機構に着目したアルツハイマー病発症機構の解明

    2017.04
    -
    2019.03

    日本学術振興会, Grant-in-Aid for Scientific Research, Research grant, Principal investigator

  • 視神経脊髄炎の動物モデルと抗アクアポリン４抗体を用いた新規治療法の開発基盤研究

    2016.04
    -
    2019.03

    日本学術振興会, Grant-in-Aid for Scientific Research, Research grant, Principal investigator

  • アルツハイマー病モデルマウスを用いたAβ蓄積から神経原繊維変化へ至る機構の解明

    2013.04
    -
    2015.03

    日本学術振興会, Grant-in-Aid for Scientific Research, Research grant, Principal investigator

  • アクアポリン4ノックアウトマウスを用いた新規視神経脊髄炎モデルの作製とその解析

    2010.04
    -
    2013.03

    日本学術振興会, Grant-in-Aid for Scientific Research, Research grant, Principal investigator

  • FALS変異SOD1導入ES細胞由来in vitroモデル神経細胞の樹立と解析

    2004.04
    -
    2006.03

    日本学術振興会, Grant-in-Aid for Scientific Research, Research grant, Principal investigator

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Courses Taught 【 Display / hide 】

  • PHARMACOLOGY

    2024

  • PHARMACOLOGY

    2023

  • PHARMACOLOGY

    2022

  • PHARMACOLOGY

    2021

  • PHARMACOLOGY

    2020

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Courses Previously Taught 【 Display / hide 】

  • 薬理学

    Keio University

    2015.04
    -
    2016.03
    , 

    Spring Semester

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Memberships in Academic Societies 【 Display / hide 】

  • 日本分子生物学会, 

    2011
    -
    Present

  • 日本神経科学学会, 

    2008
    -
    Present

  • Society for Neuroscience, 

    2003
    -
    Present

  • 日本再生医療学会, 

    2002
    -
    2010

  • 日本薬理学会, 

    1993
    -
    Present
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