E/I balance disruption in tau-related dementia

• Project/Area Number: 19K08005
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: National Institutes for Quantum Science and Technology
• Principal Investigator: Takado Yuhei 国立研究開発法人量子科学技術研究開発機構, 量子医科学研究所 脳機能イメージング研究部, 主幹研究員 (60593564)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 興奮抑制バランス / MRS / ポジトロン断層撮影 / タウオパチー / 認知症 / アストロサイト / 磁気共鳴スペクトロスコピー / アルツハイマー病 / ポジトロン断層撮像法 / 興奮・抑制バランス

Outline of Research at the Start

ヒト認知症患者における興奮・抑制バランス（E/Iバランス）破綻と脳機能障害の関係を明らかにしていくことを意識しつつ，本研究では認知症タウ病態がE/Iバランスの破綻を引き起こすメカニズムを，タウ蓄積モデルマウスを用いて明らかにすることを目指す．E/Iバランスの破綻は認知症病態のみならず筋委縮性側索硬化症などの神経難病，統合失調症といった精神疾患等，多くの脳疾患への関与が想定されている．E/Iバランスを修飾する薬剤は抗てんかん薬をはじめ多数存在する．したがって，E/Iバランスと脳病態の関連が明らかになれば，種々の脳疾患においてドラッグリポジショニングも含めた治療法開発に大きな波及効果が見込まれる．

Outline of Final Research Achievements

The aim of this study was to clarify the mechanism of E/I balance disruption in a tau protein-accumulating mouse model (rTg4510) and to find clues for the development of a treatment for dementia, and we continued the pathological evaluation using MRS, PET, and two-photon imaging as in FY2020. The current study suggested that accumulation of tau protein may contribute to a decrease in neurotransmitters and affect E/I balance, and no condition of increased excitatory neural activity was observed in the evaluation of model mice. Since we have found that disruption of E/I balance occurs early in life (Shimojo et al. J Neurosci. 2020), we believe that further evaluation at an earlier time point is also important.

Academic Significance and Societal Importance of the Research Achievements

ヒト認知症患者における興奮・抑制バランス（E/Iバランス）破綻と脳機能障害の関係を明らかにしていくことを狙い，本研究では認知症タウ病態がE/Iバランスの破綻を引き起こすメカニズムを，タウ蓄積モデルマウス（rTg4510）を用いて明らかにすることを目指した．E/Iバランスの破綻は，認知症病態のみならず種々の神経難病，統合失調症や自閉症といった精神疾患等，多くの脳疾患への関与が想定されている．E/Iバランスを修飾する薬剤は抗てんかん薬をはじめ多数存在するため、E/Iバランスと脳病態の関連が明らかになれば，種々の脳疾患においてドラッグリポジショニングも含めた治療法開発に大きな波及効果が見込まれる．

Research Products

• [Int'l Joint Research] University of Toronto(カナダ)
• [Journal Article] MRS-measured glutamate versus GABA reflects excitatory versus inhibitory neural activities in awake mice (2021)
  • Author(s): Takado Yuhei、Takuwa Hiroyuki、Sampei Kazuaki、Urushihata Takuya、Takahashi Manami、Shimojo Masafumi、Uchida Shoko、Nitta Nobuhiro、Shibata Sayaka、Nagashima Keisuke、Ochi Yoshihiro、Ono Maiko、Maeda Jun、Tomita Yutaka、Sahara Naruhiko、Near Jamie、Aoki Ichio、Shibata Kazuhisa、Higuchi Makoto
  • Journal Title: Journal of Cerebral Blood Flow & Metabolism Volume: 42 Issue: 1 Pages: 197-212
  • DOI: 10.1177/0271678x211045449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model (2021)
  • Author(s): Sato H、Takado Y、Toyoda S、Tsukamoto-Yasui M、Minatohara K、Takuwa H、Urushihata T、Takahashi M、Shimojo M、Ono M、Maeda J、Orihara A、Sahara N、Aoki I、Karakawa S、Isokawa M、Kawasaki N、Kawasaki M、Ueno S、Kanda M、Nishimura M、Suzuki K、Mitsui A、Nagao K、Kitamura A、Higuchi M
  • Journal Title: Science Advances Volume: 7 Issue: 43 Pages: 1-11
  • DOI: 10.1126/sciadv.abd5046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Selective Disruption of Inhibitory Synapses Leading to Neuronal Hyperexcitability at an Early Stage of Tau Pathogenesis in a Mouse Model. (2020)
  • Author(s): Shimojo M, Takuwa H, Takado Y, Tokunaga M, Tsukamoto S, Minatohara K, Ono M, Seki C, Maeda J, Urushihata T, Minamihisamatsu T, Aoki I, Kawamura K, Zhang MR, Suhara T, Sahara N, Higuchi M.
  • Journal Title: J Neurosci. Volume: 40 Issue: 17 Pages: 3491-3501
  • DOI: 10.1523/jneurosci.2880-19.2020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Tau protein accumulation and neurodegeneration in tauopathy model mice detected by PET and MRS (2019)
  • Author(s): Yuhei Takado, Hiroyuki Takuwa, Takuya Urushihata, Manami Takahashi, Maiko Ono, Jun Maeda, Masafumi Shimojo, Nobuhiro Nitta, Sayaka Shibata, Ichio Aoki, Naruhiko Sahara, Tetsuya Suhara, Makoto Higuchi
  • Organizer: BRAIN & BRAIN PET 2019
  • Int'l Joint Research