Elucidation of new pathogenic mechanisms of dementia and development of new therapeutic agents

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K07618
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Fukuoka University (2021); Tokyo Metropolitan Institute of Medical Science (2018-2020)
• Principal Investigator: Hosokawa Masato 福岡大学, 薬学部, 准教授 (00435116)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: タウ / ゲノム編集 / 認知症 / アルツハイマー病 / 大脳皮質基底核変性症 / ピック病 / プリオン様伝播

Outline of Final Research Achievements

In order to construct a mouse model that recapitulates the pathology of tauopathies, new mice (Tau 3R/4R mice) expressing six isoforms of tau were generated using genome editing technology to overcome the shortcomings of previous experimental tau injection mouse models. Sarkosyl-insoluble fractions were extracted from postmortem brains of dementia patients and the tau fibrils contained in these fractions were injected into the brains of Tau 3R/4R mice. We investigated whether the formation and propagation of tau accumulation pathology could be observed after a certain period of time. In the brain extracts of Alzheimer's disease-injected mice, both endogenous 3R and 4R tau accumulated, in the brain extracts of corticobasal degeneration-injected mice only 4R tau accumulated, and in the brain extracts of Pick's disease-injected mice only 3R tau accumulated. An isoform-specific, seed-dependent amplification of tau was observed.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究により、①異常タウにはアイソフォーム特異的なシード依存性凝集を引き起こす能力がある、②異常タウに伝播能がある、③脳内に注入したヒトタウ線維が種の壁を越えて内在性のマウスタウの蓄積を誘導することができる、というタウが持つプリオン様の性質が確認された。この新規マウスを用いたタウ線維注入モデルは、タウ伝播メカニズムの解明や、タウの伝播抑制作用を持つ薬剤の探索に用いることができると考えられる。