Elucidation of pathomechanism of Alzheimer's disease focusing on AQP4 function and lymphatic drainage system in the brain.

• Project/Area Number: 17K19637
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Brain sciences and related fields
• Research Institution: Keio University
• Principal Investigator: Abe Yoichiro 慶應義塾大学, 医学部(信濃町), 講師 (10317331)
• Co-Investigator(Kenkyū-buntansha): 新倉 貴子 上智大学, 理工学部, 准教授 (10301491)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: アルツハイマー病 / 脳アミロイド血管症 / アクアポリン４ / 動物モデル / アミロイドβ / 脳リンパ排泄機構 / 脳神経疾患 / 神経科学 / 遺伝子 / 認知症 / 老化

Outline of Final Research Achievements

We investigated roles of aquaporin-4 function in Alzheimer's disease pathology by crossing aquaporin-4 knockout mouse to an Alzheimer's model, 5xFAD. We found that aquaporin-4 is not involved in formation of parenchymal amyloid plaques or gliosis in response to the accumulation of amyloid plaques. In contrast, we observed that nighttime motion of 5xFAD lacking aquaporin-4 was gradually reduced from over 20 weeks of age through approximately 32 weeks of age, which is accompanied by frequent epileptiform brain activity as well as convulsions. These results suggest that in 5xFAD mice, aquaporin-4 is implicated in clearance system of interstitial neurotoxic waste after accumulation of amyloid plaques.

Academic Significance and Societal Importance of the Research Achievements

アクアポリン４はアルツハイマー病病態において老人斑の周囲にグリアが集積した結果引き起こされる神経炎症に必要であることが予想されるほか、脳内老廃物の除去にも関与する可能性が報告されていた。本研究により、アルツハイマー病モデルマウスのアクアポリン４をノックアウトすることにより、アルツハイマー病病態においてはアクアポリン４は神経炎症には関わらないことが明らかになった一方で、脳内老廃物の除去には深く関わる可能性が強く示唆された。アルツハイマー病とてんかんとの関連も報告されており、アクアポリン４を欠損した5xFADはその治療法開発のためのツールとしても用いることができる。

Research Products

• [Journal Article] Aquaporin-4-dependent glymphatic solute transport in the rodent brain (2018)
  • 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
  • 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 cells (2018)
  • 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: Scientific Reports Volume: 8 Issue: 1 Pages: 17954-17954
  • DOI: 10.1038/s41598-018-36264-9
  • Peer Reviewed / Open Access
• [Journal Article] Alteration of global protein SUMOylation in neurons and astrocytes in response to Alzheimer's disease-associated insults. (2018)
  • Author(s): Maruyama T, Wada H, Abe Y, Niikura T.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 500 Issue: 2 Pages: 470-475
  • DOI: 10.1016/j.bbrc.2018.04.104
  • Peer Reviewed
• [Journal Article] SENP1 and SENP2 regulate SUMOylation of amyloid precursor protein. (2018)
  • Author(s): Maruyama T, Abe Y, and Niikura T.
  • Journal Title: Heliyon Volume: 4 Issue: 4 Pages: e00601-e00601
  • DOI: 10.1016/j.heliyon.2018.e00601
  • Peer Reviewed / Open Access
• [Journal Article] Dissociation of blood-brain barrier disruption and disease manifestation in an aquaporin-4-deficient mouse model of amyotrophic lateral sclerosis (2017)
  • Author(s): Watanabe-Matsumoto Saori et al.
  • Journal Title: Neuroscience Research Volume: in press Pages: 48-57
  • DOI: 10.1016/j.neures.2017.11.001
  • Peer Reviewed
• [Journal Article] Humanin affects object recognition and gliosis in short-term cuprizone-treated mice. (2017)
  • Author(s): Murakami M, Nagahama M, Abe Y, Niikura T.
  • Journal Title: Neuropeptides Volume: 66 Pages: 90-96
  • DOI: 10.1016/j.npep.2017.10.002
  • Peer Reviewed
• [Remarks] 慶應義塾大学 研究者情報総覧
  • URL: http://k-ris.keio.ac.jp/Profiles/54/0005317/profile.html
• [Remarks] Keio Researchers Information System
  • URL: https://keio.pure.elsevier.com/ja/persons/yoichiro-abe
• [Remarks] Keio Researchers Information Sysstem
  • URL: https://keio.pure.elsevier.com/ja/persons/yoichiro-abe
• [Remarks] 慶應義塾大学 研究者情報総覧
  • URL: http://k-ris.keio.ac.jp/Profiles/54/0005317/profile.html