Development of imaging-based early diagnosis biomarkers of neurodegenerative disorders

• Project/Area Number: 18K07777
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52040:Radiological sciences-related
• Research Institution: National Institutes for Quantum and Radiological Science and Technology
• Principal Investigator: SHIMOJO MASAFUMI 国立研究開発法人量子科学技術研究開発機構, 放射線医学総合研究所 脳機能イメージング研究部, 研究員(任常) (20455348)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 生体脳イメージング / PET / シナプス / E/Iバランス / 神経炎症 / 神経変性 / AAV / 光イメージング / バイオマーカー / 蛍光 / レポーター

Outline of Final Research Achievements

In this study, we aimed to establish new imaging biomarkers for early detection of 1) tau aggregation, 2) inhibitory synapse, and 3) reactive astrocyte in the pathogenic cascade of Alzheimer’s disease. We found that our reporter imaging method enables us to monitor the early stage of tau aggregates. We also found that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit is critical early pathophysiology of tauopathy. Taken together, our imaging-based approach can facilitate a broad range of PET assessments for a variety of neurological disorders.

Academic Significance and Societal Importance of the Research Achievements

回路E/Iバランスの破綻や神経炎症は幅広い神経精神疾患で観察される共通病態であり、こうした病態を生体イメージングにより画像描出しながら治療効果などを検証する事が可能となる事で、画期的な創薬研究に繋がる。レポーターイメージング法の更なる発展性を追求するとともに、炎症性アストロサイトの生体イメージング技術開発に引き続き取り組む事を通じて、より複雑な脳疾患病態メカニズム解明に向けた研究プラットフォーム構築が期待された。

Research Products

• [Journal Article] Distinct microglial response against Alzheimer's amyloid and tau pathologies characterized by P2Y12 receptor (2021)
  • Author(s): 93.Maeda J. Sahara N.（他１９名）
  • Journal Title: Brain Communications Volume: 3 Issue: 1 Pages: 1-19
  • DOI: 10.1093/braincomms/fcab011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer’s and Non-Alzheimer’s Disease Tauopathies (2021)
  • Author(s): Tagai K, Ono M, Kubota M, Kitamura S, Takahata K, Seki C, Takado Y, Shinotoh H, Sano Y, Yamamoto Y, Matsuoka K, Takuwa H, Shimojo M, (24人省略), Shimada H.
  • Journal Title: Neuron Volume: 109 Issue: 1 Pages: 42-58
  • DOI: 10.1016/j.neuron.2020.09.042
  • 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
• [Journal Article] Synaptotagmin-11 mediates a vesicle trafficking pathway that is essential for development and synaptic plasticity (2019)
  • Author(s): Shimojo Masafumi、Madara Joseph、Pankow Sandra、Liu Xinran、Yates John、S?dhof Thomas C.、Maximov Anton
  • Journal Title: Genes & Development Volume: 33 Issue: 5-6 Pages: 365-376
  • DOI: 10.1101/gad.320077.118
  • Peer Reviewed
• [Presentation] 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
  • Organizer: 日本神経化学会(WEB開催)
  • Invited
• [Presentation] 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.
  • Organizer: 日本神経科学会(WEB開催)
• [Presentation] 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.
  • Organizer: FENS Forum 2020 (Online)
  • Int'l Joint Research
• [Presentation] Genetically encoded reporter for bimodal optical and PET imaging in the mammalian brain (2018)
  • Author(s): Masafumi Shimojo, et al
  • Organizer: SfN2018
  • Int'l Joint Research
• [Presentation] In vivo assessment of synaptic properties in rTg4510 tauopathy transgenic mouse model by positron emission tomography (2018)
  • Author(s): Masafumi Shimojo, Hiroyuki Takuwa, Yuhei Takado, Masaki Tokunaga, Urushihata Takuya, Tsukamoto Satoshi, Jun Maeda, Takeharu Minamihisamatsu, Ming-Rong Zhang, Ichio Aoki, Tetsuya Suhara, Naruhiko Sahara, Makoto Higuchi
  • Organizer: 第37回認知症学会
• [Presentation] Genetically encoded reporter for bimodal optical and PET imaging in the mammalian brain (2018)
  • Author(s): Masafumi Shimojo, et al
  • Organizer: 第41回 日本神経科学大会
• [Presentation] Genetically encoded reporter for bimodal optical and PET imaging in the mammalian brain (2018)
  • Author(s): Masafumi Shimojo, et al
  • Organizer: FENS Forum2018
  • Int'l Joint Research