Rho-kinase ROCK Inhibitors Reduce Oligomeric Tau Protein

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09235
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: University of Fukui
• Principal Investigator: Hamano Tadanori 福井大学, 学術研究院医学系部門, 准教授 (40334817)
• Co-Investigator(Kenkyū-buntansha): 白藤 法道 福井大学, 学術研究院医学系部門, 助教 (40529319) ; 吉田 裕孝 国立研究開発法人国立長寿医療研究センター, 共同利用推進室, 研究生 (70646570)
• Research Collaborator: Fujita Youshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: アルツハイマー病 / タウ蛋白 / オートファジー

Outline of Final Research Achievements

Neurofibrillary tangles (NFTs), pathological hallmarks of Alzheimer’s disease (AD), consist of highly phosphorylated tau. We previously reported that pitavastatin decreases the total and phosphorylated tau. The reduction of tau was considered to be due to Rho-associated coiled coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. We have examined the effects of ROCK inhibitors on tau phosphorylation in detail by using cell culture model of tauopathy,and a mouse model of tauopathy . The levels of phosphorylated tau, and oligomeric tau were reduced by the ROCK inhibitors. ROCK inhibitor inactivated tau kinases (GSK3beta, Cdk5). Autophagy, which is important for the degradation of tau was activated. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic tau protein in tauopathies, including AD.

Free Research Field

アルツハイマー病

Academic Significance and Societal Importance of the Research Achievements

本研究により、ROCK阻害薬はアルツハイマー病でみられる高度にリン酸化し、重合したタウ蛋白を減少させる可能性が示された。またこの効果はタウ蛋白リン酸化酵素(GSK3β、Cdk5)の不活性化、およびタウ蛋白分解経路であるオートファジーの活性化による可能性がしめされた。
本研究はアルツハイマー病をはじめとするタウオパチーの新しい治療法を提示する可能性があり、トランスレーショナルリサーチへの応用が期待され、学術的、および社会的に極めて重要である。