Establishment of brain protein aging models; human iPS cell model and non-human primate model

2018 Fiscal Year Final Research Report

• Project Area: Prevention of brain protein aging and dementia
• Project/Area Number: 26117007
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Keio University
• Principal Investigator: Okano Hideyuki 慶應義塾大学, 医学部(信濃町), 教授 (60160694)
• Co-Investigator(Renkei-kenkyūsha): SHIOZAWA Seiji
• Research Collaborator: IKEUCHI Takeshi
• Project Period (FY): 2014-07-10 – 2019-03-31
• Keywords: iPS細胞 / 認知症 / タウタンパク質 / ゲノム編集 / マーモセット

Outline of Final Research Achievements

For the potential development of novel therapeutic strategies for tauopathies, our group established a tauopathy model bearing tau mutations associated with frontotemporal dementia with parkinsonism-17 (FTDP-17) for investigating tau pathology and for usage in drug screening.
For this purpose, we generated iPSCs from 2 frontotemporal dementia patients of a Japanese pedigree bearing the tau R406W mutation. To examine the phenotypes in neurons, we developed efficient cortical neural differentiation methods for iPSCs using small molecules. In this neuronal culture, the mutant tau exhibited reduced phosphorylation levels and was increasingly fragmented by calpain. Furthermore, the mutant tau protein was mislocalized and the axons of the patient-derived neurons displayed morphological and functional abnormalities, which were rescued by microtubule stabilization. Collectively, our findings provide new mechanistic insight into tau pathology and a potential for therapeutic intervention.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

認知症を始めとする神経変性疾患は人口の高齢化に伴い増加の一途を辿っており、その克服は人類が直面している最も重要な課題の１つと言える。本研究では、様々な神経変性疾患の原因となるタウタンパク質に着目し、このタンパク質をコードする遺伝子の変異によって起こる家族性前頭側頭型認知症患者からiPS細胞を樹立し、神経細胞へと分化させた。この神経細胞を健常なコントロールと比較することで、その病態の一端を明らかにした。本研究によって確立したモデルを用いることで、タウタンパク質を起因とする神経変性疾患の治療薬や発症を抑える化合物のスクリーニングなど、創薬や新たな治療法の開発への発展が期待される。