Rho-kinase ROCK Inhibitors Reduce Oligomeric Tau Protein

• 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
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: アルツハイマー病 / タウ蛋白 / オートファジー / ROCK阻害薬 / オリゴマータウ / GSK3β / オリゴマー / 内科 / 老年医学

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.

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。

Research Products

• [Int'l Joint Research] Mayo Clinic Jacksonville/Michigan State University(米国)
• [Journal Article] Apolipoprotein E and clusterin inhibit the early phase of amyloid-β aggregation in an in vitro model of cerebral amyloid angiopathy (2019)
  • Author(s): Endo Y, Hasegawa K, Nomura R, Arishima H, Kikuta K, Yamashita T, Inoue Y, Ueda M, Ando Y, Wilson MR, Hamano T, Nakamoto Y, Naiki H.
  • Journal Title: Acta Neuropathologica Communications Volume: 7 Issue: 1 Pages: 12-12
  • DOI: 10.1186/s40478-019-0662-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cladophialophora bantiana infection mimicking neuromyelitis optica. (2019)
  • Author(s): Enomoto S, Shigemi H, Kitazaki Y, Ikawa M, Yamamura O, Hamano T, Tai K, Iwasaki H, Koizumi H, Hasegawa M, Takeda K, Nakamoto Y.
  • Journal Title: J Neurol Sci. Volume: 399: Pages: 169-171
  • DOI: 10.1016/j.jns.2018.12.013
  • Peer Reviewed
• [Journal Article] The Implications of Autophagy in Alzheimer's Disease. (2018)
  • Author(s): Hamano T, Hayashi K, Shirafuji N, Nakamoto Y.
  • Journal Title: Curr Alzheimer Res. Volume: 15(14) Issue: 14 Pages: 1283-1296
  • DOI: 10.2174/1567205015666181004143432
  • Peer Reviewed
• [Journal Article] Homocysteine Increases Tau Phosphorylation,Truncation and Oligomerization. (2018)
  • Author(s): Shirafuji N, Hamano T, Yen SH, Kanaan NM, Yoshida H, Hayashi K, Ikawa M,Yamamura O, Kuriyama M, Nakamoto Y.
  • Journal Title: Int J Mol Sci. Volume: 19(3) Issue: 3 Pages: 17-17
  • DOI: 10.3390/ijms19030891
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Increased adiponectin is associated with cerebral white matter lesions in theelderly with cognitive impairment. (2018)
  • Author(s): Fujita Y, Toyomoto T, Sakoh-Goshima T, Kohno Y, Okada M, Hamano T, Nakamoto Y.
  • Journal Title: Metab Brain Dis Volume: May 11 Issue: 4 Pages: 1385-1388
  • DOI: 10.1007/s11011-018-0247-x
  • Peer Reviewed / Open Access
• [Journal Article] Arterial spin labeling MR imaging for the clinical detection of cerebellar hypoperfusion in patients with spinocerebellar degeneration. (2018)
  • Author(s): Ikawa M, Kimura, H, Kitazaki Y, Sugimoto K, Matsunaga A, Hayashi K, Yamamura O, Tsujikawa T, Hamano T, Yoneda M, Okazawa H, Nakamoto Y.
  • Journal Title: J Neurol Sci Volume: 394 Pages: 58-62
  • DOI: 10.1016/j.jns.2018.09.007
  • Peer Reviewed
• [Journal Article] Premorbid physical activity is modestly associated with gait independence after a stroke: an exploratory study. (2018)
  • Author(s): Yamaguchi T, Yamamura O, Hamano T, Murakita K, Nakamoto Y.
  • Journal Title: Eur Rev Aging Phys Act. Volume: 15 Issue: 1 Pages: 18-18
  • DOI: 10.1186/s11556-018-0208-8
  • Peer Reviewed
• [Journal Article] Ultrasound cardiography examinations detect victims' long-term realized and potential consequences after major disasters: a case-control study. (2018)
  • Author(s): Onishi H, Yamamura O, Ueda S, Shibata M, Enomoto S, Maeda F, Tsubouchi H, Hirobe T, Shimizu S, Hanzawa K, Hamano T, Nakamoto Y, Hayashi H, Terasawa H.
  • Journal Title: Environ Health Prev Med. Volume: 23(1) Issue: 1 Pages: 37-37
  • DOI: 10.1186/s12199-018-0721-4
  • NAID: 50012994947
  • Peer Reviewed
• [Journal Article] Rho-ROCK阻害薬によるタウ蛋白 オリゴマー形成抑制機構の解明 (2018)
  • Author(s): 濱野忠則、白藤法道、林浩嗣、佐々木宏仁、中本安成.
  • Journal Title: 細胞 Volume: 50(6) Pages: 340-343
• [Journal Article] ROCK阻害薬によるタウ蛋白オリゴマー形成抑制機構 (2018)
  • Author(s): 濱野忠則、白藤法道、林浩嗣、佐々木宏仁、中本安成
  • Journal Title: アグリバイオ Volume: 2(8) Pages: 790-794
  • NAID: 40021807815
• [Journal Article] 「古くて新しい神経感染症 真菌性髄膜炎の克服にむけて」 真菌性髄膜炎の疫学と長期予後． (2018)
  • Author(s): 濱野 忠則, 上野 亜佐子
  • Journal Title: NEUROINFECTION Volume: 23(1) Pages: 90-97
• [Journal Article] 第1回内科医が身に付ける認知症患者の対処法. (2018)
  • Author(s): 濱野忠則、上野亜佐子、伊藤達彦、山村修、山本雅之、他4名.
  • Journal Title: 日内会誌 Volume: 107: Pages: 779-784
  • NAID: 130007630012
  • Peer Reviewed
• [Journal Article] Rho-ROCK阻害薬によるタウ蛋白オリゴマー形成抑制機構の解明 (2018)
  • Author(s): 濱野忠則、白藤 法道、林 浩嗣、佐々木 宏仁、中本 安成
  • Journal Title: 細胞 Volume: 50 Pages: 340-343
  • Peer Reviewed
• [Journal Article] Influenza A (H3N2)-induced rhabdomyolysis complicating anterior compartment syndrome: Serial changes in muscle MRI T2 fat suppression imaging. (2017)
  • Author(s): Hamano T, Matsunaga A, Yamamura O, Nakamura M, Kawamura Y, Higuchi I, Kuriyama M, Nakamoto Y.
  • Journal Title: eNeurologicalSci Volume: 7 Pages: 15-17
  • DOI: 10.1016/j.ensci.2017.03.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Limbic encephalitis associated with anti-NH2-terminal of α-enolase antibodies: A clinical subtype of Hashimoto encephalopathy. (2017)
  • Author(s): Kishitani T, Matsunaga A, Ikawa M, Hayashi K, Yamamura O, Hamano T, Watanabe O, Tanaka K, Nakamoto Y, Yoneda M
  • Journal Title: Medicine Volume: 96(10) Issue: 10 Pages: e6181-e6181
  • DOI: 10.1097/md.0000000000006181
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A case of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody-positive paraneoplastic necrotizing myopathy associated with advanced gastric cancer that responded to intravenous immunoglobulin therapy (2017)
  • Author(s): Yamaguchi T, Matsunaga A, Ikawa M, Shirafuji N, Nishino I, Hamano T.
  • Journal Title: Rinsho Shinkeigaku Volume: 57 Issue: 3 Pages: 118-123
  • DOI: 10.5692/clinicalneurol.cn-000982
  • NAID: 130005494165
  • ISSN: 0009-918X, 1882-0654
  • Peer Reviewed
• [Journal Article] Pioglitazone prevents tau oligomerization. (2016)
  • Author(s): Hamano T, Shirafuji N, Makino C, Yen SH, Kanaan NM, Ueno A, Suzuki J, Ikawa M, Matsunaga A, Yamamura O, Kuriyama M, Nakamoto Y.
  • Journal Title: Biochem Biophys Res Commun Volume: 478 Issue: 3 Pages: 1035-1042
  • DOI: 10.1016/j.bbrc.2016.08.016
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Muscle MRI of the Upper Extremity in the Myotonic Dystrophy Type 1 (2016)
  • Author(s): K. Hayashi, T. Hamano, Y. Kawamura, H. Kimura, A. Matsunaga, M. Ikawa, O. Yamamura, T. Mutoh, I. Higuchi, M. Kuriyama, Y. Nakamoto
  • Journal Title: Eur Neurol Volume: 76 Issue: 1-2 Pages: 87-94
  • DOI: 10.1159/000448328
  • Peer Reviewed / Open Access
• [Presentation] TRAINING COURSE OF EVALUATION AND MANAGEMENT OF DEMENTIA FOR PRIMARY CARE PHYSICIANS. (2018)
  • Author(s): Hamano T, Nagata M, Matsubara R, Ito T, Ikebata Y, Ibe A, Enomoto S
  • Organizer: Alzheimer Association International Conference 2018 in Chicago, USA, July 22-26, 2018
  • Int'l Joint Research
• [Presentation] CSF TAU PROTEIN IN AUTOIMMUNE ENCEPHALIIS PATIENTS. (2018)
  • Author(s): Kitazaki Y, Hamano T, Ueno A, Asano R, Sasaki H, Enomoto S, Yamamura O
  • Organizer: Alzheimer's Association International conference AAIC 2018, Chicago, July 22-26, 2018
  • Int'l Joint Research
• [Presentation] Special Clinical Session3（頭痛の診断と治療のポイント3)副鼻腔炎およびTolosa Hunt症候群による頭痛の診断と治療 (2018)
  • Author(s): 濱野忠則
  • Organizer: Headache Master School Japan 2018 in Toyama
  • Invited
• [Presentation] EFFECTIVENESS OF PITAVASTATIN IN PATIENTS WITH MILD ALZHEIMER'S DISEASE AND HYPERLIPIDEMIA (2017)
  • Author(s): Hamano, T., Hayashi, K., Ueno, A., Shirafuji, N., Fujita, Y., et al.,
  • Organizer: AAIC 2017
  • Int'l Joint Research
• [Presentation] Dopamine transporter imaging (DAT-SPECT) In Pisa syndrome with Parkisnon’s disease. (2017)
  • Author(s): Sasaki, H., Hamano, T., Kitazaki, Y., Yamaguchi, T., Endo, Y., Enomoto, S., Hayashi, K.
  • Organizer: World Congress of Neurology 2017
  • Int'l Joint Research
• [Presentation] Arterial spin labeling MRI in sporadic Creutzfeldt-Jakob disease. (2017)
  • Author(s): Kitazaki, Y., Hamano, T., Sasaki, H., Yamaguchi, T., Endo, Y., Enomoto, S.,Hayashi, K.
  • Organizer: World Congress of Neurology 2017
  • Int'l Joint Research
• [Presentation] HYPOPERFUSION-INDUCED TAU HYPERPHOSPHORYLATION EXTENDS TO THE NON-HYPOPERFUSED AREA IN MOUSE BRAIN. (2016)
  • Author(s): Fujita, Y., Hamano, T., Shirafuji, N., & Nakamoto, Y. .
  • Organizer: Alzheimer's Association International Conference (AAIC) 2016
  • Place of Presentation: Toronto, Canada
  • Int'l Joint Research
• [Presentation] EFFICACY OF A SHORT QUESTIONNAIRE FOR SCREENING OF EARLY STAGE OF DEMENTIA: TRIAL IN FUKUI PREFECTURE, JAPAN. (2016)
  • Author(s): Hamano, T., Fujita, Y., Nagata, M., Ito, T., et al.
  • Organizer: Alzheimer's Association International Conference (AAIC) 2016
  • Place of Presentation: Toronto, Canada
  • Int'l Joint Research
• [Book] アルツハイマー病 認知症疾患 臨床医のための実践ガイド (2017)
  • Author(s): 小野賢二郎、徳田隆彦、富田泰輔、濱野忠則、上野亜佐子、他
  • Total Pages: 248
  • Publisher: 朝倉書店
  • ISBN: 9780323286619
• [Book] 認知症診療実践ハンドブック (2017)
  • Author(s): 山田正仁、坂井健二、小野賢二郎、濱野忠則、林浩嗣他
  • Total Pages: 368
  • Publisher: 中外医学社