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Physiology relevance of cerebral lymphatic flow and the mechanism of higher brain dysfunction due to its breakdown

Research Project

Project/Area Number 18H02606
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 48030:Pharmacology-related
Research InstitutionKeio University

Principal Investigator

Masato Yasui  慶應義塾大学, 医学部(信濃町), 教授 (90246637)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywordsアクアポリン / 脳リンパ排泄 / 非線形光学 / アルツハイマー病 / 脳のリンパ流 / アクアポリン 脳リンパ液 アルツハイマー病 / 脳リンパ流 / 脳浮腫 / グリア
Outline of Final Research Achievements

Lymphatic flow was thought to be absent in the brain, but it has recently been shown that glial cells, especially aquaporin 4 (AQP4), may play a role. Here we succeeded in visualizing the water dynamics of brain tissue by observing the water molecules themselves using a nonlinear optical microscope that we originally developed.
Abnormal lymphatic excretion in the brain leads to abnormal accumulation of amyloid β (Aβ), and its involvement with Alzheimer's disease is suspected. By crossing an Alzheimer's disease mouse model with an AQP4-deficient mouse, we found that the mice showed marked abnormal behavior at an early stage. These results are expected to lead to the development of new early diagnosis and treatment methods for Alzheimer's disease.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、AQP4の発現や機能を維持することで、アルツハイマー病の進行を遅らせ、更には改善を図るというこれまでとは全く異なる治療戦略の創出を促す可能性がある。また、脳のリンパ排泄機構を直接可視化する技術の向上をもたらすと考えられ、将来的な特異的な造影技術の開発と相まって、様々な脳疾患の診断法の発展、中枢神経に作用する薬物の動態の可視化及び制御に関する革新的な技術開発につながると期待される。脳のリンパ排泄機構の理解は脳アミロイド血管症やその他の神経変性疾患の理解にもつながり、認知症にとどまらず今後益々高齢化が進む我が国の社会的負担を大幅に軽減するとともに国民の福祉の向上にも大きく寄与する。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(25 results)

All 2021 2020 2019 2018

All Journal Article (13 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 13 results,  Open Access: 12 results) Presentation (12 results) (of which Invited: 6 results)

  • [Journal Article] Monitoring the morphological evolution of giant vesicles by azo dye-based sum-frequency generation (SFG) microscopy2020

    • Author(s)
      Momotake Atsuya、Mizuguchi Takaha、Hishida Mafumi、Yamamoto Yasuhiko、Yasui Masato、Nuriya Mutsuo
    • Journal Title

      Colloids and Surfaces B: Biointerfaces.

      Volume: 186 Pages: 110716-110716

    • DOI

      10.1016/j.colsurfb.2019.110716

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulation of AQP4 in the Central Nervous System.2020

    • Author(s)
      Vandebroek AA, Yasui M.
    • Journal Title

      Int J Mol Sci.

      Volume: 26;21(5) Pages: 1603-1603

    • DOI

      10.3390/ijms21051603

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of increased daily water intake and hydration on health in Japanese adults.2020

    • Author(s)
      Nakamura Y, Watanabe H, Tanaka A, Yasui M, Nishihira J, Murayama N.
    • Journal Title

      Nutrients

      Volume: 23;12(4) Pages: 1191-1191

    • DOI

      10.3390/nu12041191

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model2020

    • Author(s)
      Abe Y, Ikegawa N, Yoshida K, Muramatsu K, Hattori S, Murakami M, Tanaka T, Goda W, Hashimoto T, Miyakawa T, Iwatsubo T, Hata J, Niikura T, Yasui M, et al.
    • Journal Title

      Acta Neuropathol. Commun.

      Volume: 8 Pages: 67-67

    • DOI

      10.1186/s40478-020-00936-3

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sleep stage detection using only heart rate.2020

    • Author(s)
      Mitsukura Y, Fukunaga K, Yasui M, Mimura M.
    • Journal Title

      Health Informatics J

      Volume: 26(1) Pages: 376-387

    • DOI

      10.1177/1460458219827349

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sleep Stage Estimation from Bed Leg Ballistocardiogram Sensors.2020

    • Author(s)
      Mitsukura Y, Fukunaga K, Yasui M, Mimura M.
    • Journal Title

      Sensors (Basel)

      Volume: 5;20(19)

    • DOI

      10.3390/s20195688

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of aquaporin-3 in macrophages by a monoclonal antibody as potential therapy for liver injury.2020

    • Author(s)
      Hara-Chikuma M, Tanaka M, Verkman A.S, Yasui M.
    • Journal Title

      Nat Commun.

      Volume: 9;11(1) Pages: 5666-5666

    • DOI

      10.1038/s41467-020-19491-5

    • NAID

      130007811921

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of compounds in red wine that effectively upregulate aquaporin-3 as a potential mechanism of enhancement of skin moisturizing.2020

    • Author(s)
      Nakamura Y, Tsuchiya T, Hara-Chikuma M, Yasui M, Fukui Y.
    • Journal Title

      Biochem Biophys

      Volume: Rep. 23;24: Pages: 100864-100864

    • DOI

      10.1016/j.bbrep.2020.100864

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adrenergic receptor antagonism induces neuroprotection and facilitates recovery from acute ischemic stroke2019

    • Author(s)
      Monai Hiromu、Wang Xiaowen、Yahagi Kazuko、Lou Nanhong、Mestre Humberto、Xu Qiwu、Abe Yoichiro、Yasui Masato、Iwai Youichi、Nedergaard Maiken、Hirase Hajime
    • Journal Title

      Proc. Natl. Acad. Sci. USA.

      Volume: 116 Pages: 11010-11019

    • DOI

      10.1073/pnas.1817347116

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Aquaporin 4 Suppresses Neural Hyperactivity and Synaptic Fatigue and Fine-Tunes Neurotransmission to Regulate Visual Function in the Mouse Retina2019

    • Author(s)
      Ozawa Yoko、Toda Eriko、Kawashima Hirohiko、Homma Kohei、Osada Hideto、Nagai Norihiro、Abe Yoichiro、Yasui Masato、Tsubota Kazuo
    • Journal Title

      Mol Neurobiol.

      Volume: 56 Pages: 8124-8135

    • DOI

      10.1007/s12035-019-01661-2

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characterization of Intra/Extracellular Water States Probed by Ultrabroadband Multiplex Coherent Anti-Stokes Raman Scattering (CARS) Spectroscopic Imaging.2019

    • Author(s)
      Nuriya M, Yoneyama H, Takahashi K, Leproux P, Coudrc V, Yasui M, Kano H.
    • Journal Title

      The Journal of Physical Chemistry A

      Volume: 123 (17) Pages: 3928-3934

    • DOI

      10.1021/acs.jpca.9b03018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Aquaporin-4-dependent glymphatic solute transport in the rodent brain2018

    • Author(s)
      H. Mestre*, LM. Hablitz*, ALB. Xavier*, W. Feng*, W. Zou*, T. Pu*, H. Monai*, G. Murlidharan*, RM. Castellanos Rivera*, MJ. Simon*, MM. Pike*, V. Pla*, T. Du*, BT. Kress*, X. Wang, BA. Plog, AS. Thrane, I. Lundgaard, Y. Abe, M. Yasui, JH. Thomas, M. Xiao, H. Hirase, A. Asokan, JJ. Iliff, M. Nedergaard
    • Journal Title

      elife

      Volume: 7

    • DOI

      10.7554/elife.40070

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Comparison of diffusion-weighted MRI and anti-Stokes Raman scattering (CARS) measurements of the inter-compartmental exchange-time of water in expression-controlled aquaporin-4 cells2018

    • Author(s)
      Obata Takayuki、Kershaw Jeff、Tachibana Yasuhiko、Miyauchi Takayuki、Abe Yoichiro、Shibata Sayaka、Kawaguchi Hiroshi、Ikoma Yoko、Takuwa Hiroyuki、Aoki Ichio、Yasui Masato
    • Journal Title

      Sci Rep.,

      Volume: 8 Pages: 17954-17954

    • DOI

      10.1038/s41598-018-36264-9

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] アクアポリンと脳水流のダイナミクス2021

    • Author(s)
      安井正人
    • Organizer
      第15回北海道大学医学研究院連携研究センター研究成果発表会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Water biology and medicine -roles of aquaporins in biological system2021

    • Author(s)
      安井正人
    • Organizer
      The 4th Aquaphotomics International Conference
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] アクアポリン4の機能と神経変性疾患2020

    • Author(s)
      安井正人
    • Organizer
      名古屋分子標的イメージングセミナー(エーザイ㈱)
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 脳内における水のダイナミクスとアクアポリン42020

    • Author(s)
      安井正人
    • Organizer
      日本神経病理学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 脳内における水のダイナミクスとアクアポリン42020

    • Author(s)
      安井正人
    • Organizer
      WEB講演会 視神経炎 Up To Date (帝人ヘルスケア)
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ALSの病態進行におけるグリアリンパ系の関与Involvement of glymphatic system in amyotrophic lateral sclerosis pathology2020

    • Author(s)
      廣瀬 美嘉子、麻野 珠都、設楽 周聖、阿部 陽一郎、安井 正人、徳田 栄一、古川 良明、三澤 日出巳
    • Organizer
      第93回薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] アクアポリン4欠損に感受性のアミロイド沈着・神経炎症に続いて起こる第二の神経変性過程2019

    • Author(s)
      阿部 陽一郎、池川 夏実、村上 峰宇、田中 拓海、新倉 貴子、村松 恭祐、山田 薫、橋本 唯史、後藤 元人、山本 大地、川井 健司、合田 和香美、吉田 慶多朗、服部 聡子、宮川 剛、田中 謙二、三村 將、岩坪 威、秦 順一、安井 正人
    • Organizer
      第42回日本神経科学大会 第62回日本神経化学会大会(新潟)
    • Related Report
      2019 Annual Research Report
  • [Presentation] Aquaporin-4の欠損はタウの蓄積と神経細胞死を増悪させる2019

    • Author(s)
      石田和久、山田薫、橋本唯史、阿部陽一郎、安井正人、岩坪威
    • Organizer
      第38回日本認知症学会学術集会(東京)
    • Related Report
      2019 Annual Research Report
  • [Presentation] アクアポリン4の抗体依存的内在化後のライソゾームへの輸送に於ける277番目のチロシン及び259番目のリジンから270番目のアラニンの間の領域の役割2019

    • Author(s)
      阿部陽一郎、鈴木亮介、合田和香美、安井正人
    • Organizer
      第42回日本分子生物学会年会(福岡)
    • Related Report
      2019 Annual Research Report
  • [Presentation] アクアポリン4は水中毒によるparavascular spaceの閉塞と脳神経活動の低下を促進するAquaporin-4 facilitates paravascular space closure and neuronal activity reduction after water intoxication2019

    • Author(s)
      石川 智愛、畝川 美悠紀、冨田 裕、中原 仁、安井 正人
    • Organizer
      第93回薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 5xFADにおけるアミロイドβ蓄積や神経炎症以外に対するAQP4の神経保護的役割A neuroprotective role of aquaporin-4 against other than amyloid β deposition or neuroinflammation in the 5xFAD transgenic mice model.2019

    • Author(s)
      阿部 陽一郎、池川 夏実、村上 峰宇、田中 拓海、新倉 貴子、村松 恭祐、山田 薫、橋本 唯史、後藤 元人、山本 大地、川井 健司、合田 和香美、吉田 慶多朗、服部 聡子、宮川 剛、田中 謙二、三村 將、岩坪 威、秦 順一、安井 正人
    • Organizer
      第93回薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] アクアポリン研究の最前線~病態生理の理解から新たな診断・治療法の開発まで~2019

    • Author(s)
      安井 正人
    • Organizer
      In vivo実験医学シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited

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Published: 2018-04-23   Modified: 2022-01-27  

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