The expression analysis of Tau protein in hiPSC-derived neurons or directly converted neurons from fibroblasts

• Project/Area Number: 17H07087
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Keio University
• Principal Investigator: Maeda Sumihiro 慶應義塾大学, 医学部(信濃町), 講師 (70443025)
• Research Collaborator: TAKASHIMA Akihiko 学習院大学, 理学部, 教授 (00154774)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: タウタンパク質 / 神経変性疾患 / 老化 / 脳 / アルツハイマー病 / FTDP-17 / 脳神経疾患

Outline of Final Research Achievements

Tau protein accumulation is a pathological hallmark observed in various neurodegenerative diseases including Alzheimer’s disease (AD). Tau accumulation at lesser extent is even observed in normal aging. Recent failures in the therapy development of AD based on mouse models implied the requirement of the pathomechanism validation using human cells for human diseases. Thus, we established neuronal cultures derived from human induced pluripotent stem cell or directly converted neurons from fibroblast to conserve the aging signature of the cells to model tau- and aging-dependent diseases including AD.

Academic Significance and Societal Importance of the Research Achievements

タウタンパク質の蓄積は、アルツハイマー病をはじめとする様々な神経変性疾患において観察されるのみならず、正常老化においても観察される現象であり、脳機能の年齢依存的な低下と深い関連性があるとされている。そのタウタンパク質の機能解析を、年齢依存的変化がキャンセルされたiPS細胞由来神経、および年齢依存的変化が保存されている体細胞から直接誘導された神経において行うことは、年齢とタウタンパク質の機能異常を解明する上で、非常に重要な系であった。今後、この系を用いて、タウタンパク質の機能異常を解明し、その治療薬を開発出来れば、超高齢社会を迎える日本においては、社会経済的にも非常に大きな意味がある。

Research Products

• [Int'l Joint Research] The J. David Gladstone Institute(米国)
• [Journal Article] Methylene Blue Inhibits Formation of Tau Fibrils but not of Granular Tau Oligomers: A Plausible Key to Understanding Failure of a Clinical Trial for Alzheimer’s Disease (2019)
  • Author(s): Soeda Yoshiyuki、Saito Marino、Maeda Sumihiro、Ishida Kohki、Nakamura Akira、Kojima Shuichi、Takashima Akihiko
  • Journal Title: Journal of Alzheimer's Disease Volume: 68 Issue: 4 Pages: 1677-1686
  • DOI: 10.3233/jad-181001
  • Peer Reviewed
• [Journal Article] Frontotemporal dementia with Parkinsonism linked to chromosome-17 mutations enhance tau oligomer formation (2018)
  • Author(s): Maeda Sumihiro、Sato Yuhei、Takashima Akihiko
  • Journal Title: Neurobiology of Aging Volume: 69 Pages: 26-32
  • DOI: 10.1016/j.neurobiolaging.2018.04.014
  • Peer Reviewed / Open Access
• [Journal Article] Neuronal levels and sequence of tau modulate the power of brain rhythms (2018)
  • Author(s): Das Melanie、Maeda Sumihiro、Hu Bozhong、Yu Gui-Qiu、Guo Weikun、Lopez Isabel、Yu Xinxing、Tai Chao、Wang Xin、Mucke Lennart
  • Journal Title: Neurobiology of Disease Volume: 117 Pages: 181-188
  • DOI: 10.1016/j.nbd.2018.05.020
  • Int'l Joint Research
• [Journal Article] タウタンパク質研究における新たな潮流 (2018)
  • Author(s): 前田純宏
  • Journal Title: オベリスク Volume: 23 Pages: 9-13
• [Presentation] Aggregation dependent and independent pathogenesis of Tau protein (2018)
  • Author(s): Sumihiro Maeda
  • Organizer: Invited seminar at German Center for Neurodegenerative Disease
  • Int'l Joint Research / Invited
• [Presentation] Neuronal Levels and Sequence of Tau Modulate the Power of Brain Rhythms (2018)
  • Author(s): Sumihiro Maeda
  • Organizer: Tau meeting 2018 at Kyoto
  • Invited
• [Presentation] Methylene blue inhibits formation of tau fibrils but not granular tau oligomers (2018)
  • Author(s): M. SAITO, Y. SOEDA, S. MAEDA, A. TAKASHIMA
  • Organizer: SfN 2018
  • Int'l Joint Research
• [Presentation] Modeling benign adult familial myoclonic epilepsy (BAFME) using patient specific induced pluripotent stem cells (iPSCs)- derived neurons (2018)
  • Author(s): Y. NAGASAKO, S. MAEDA, M. ISHIKAWA, H. ISHIURA, T. TODA, S. TSUJI, H. OKANO
  • Organizer: SfN 2018
  • Int'l Joint Research
• [Presentation] In vitro disease modeling of the FTDP-17 TAU R406W mutation using patient-derived iPSCs (2018)
  • Author(s): M. NAKAMURA, H. WATANABE, S. SHIOZAWA, S. MAEDA, S.-I. HISANAGA3, N. SAHARA, T. KIMURA, T. MIYASAKA, A. TAKASHIMA, T. IKEUCHI, H. OKANO
  • Organizer: SfN 2018
  • Int'l Joint Research
• [Presentation] Physiological role of dendritic tau protein on AMPA receptor dynamics (2018)
  • Author(s): M. KANATANI, H. BANNAI, Y. SOEDA, S. MAEDA, A. TAKASHIMA
  • Organizer: SfN 2018
  • Int'l Joint Research
• [Presentation] Aggregation-dependent and independent pathogenesis of Tau protein (2018)
  • Author(s): Sumihiro Maeda
  • Organizer: Keio-Cologne Symposium on Aging and Longevity
  • Int'l Joint Research / Invited
• [Presentation] Aggregation-dependent and independent pathogenesis of Tau protein (2017)
  • Author(s): Sumihiro Maeda
  • Organizer: Karolinska Institute Joint Summer Program 2017 "Brain Aging"
  • Int'l Joint Research / Invited
• [Presentation] Aggregation-dependent and independent pathogenesis of Tau protein (2017)
  • Author(s): Sumihiro Maeda
  • Organizer: タウ研究会2017
  • Int'l Joint Research / Invited