Tau oligomerization by BioMetals

• Project/Area Number: 19K07909
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• 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)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: バイオメタル / アルツハイマー病 / タウ蛋白 / リン酸化 / オートファジー / プロテアソーム / タウ / クリオキノール / タウ蛋白リン酸化 / タウオリゴマー / タウ蛋白リン酸化酵素 / オリゴマー

Outline of Research at the Start

Zn、Cuといった生物必須微量元素（バイオメタル）はアルツハイマー病(AD)脳で高濃度に存在し、ADでみられる神経原線維変化の構成要素：タウ蛋白のリン酸化を促進する可能性が示唆されている。申請者らはバイオメタルがタウオリゴマー形成を促進する機序、およびキレート剤がオリゴマー形成を抑制する機序について、TET-OFF誘導系を導入し野生型タウを発現する神経系細胞モデルを用いて詳細に検討する。同様にまた変異型タウモデルマウス(P301L)にバイオメタル、あるいはキレート剤を投与することによるタウオリゴマー形成に及ぼす影響、AD剖検脳でのバイオメタルとタウオリゴマーとの共存ついても検証する

Outline of Final Research Achievements

Neurofibrillary tangles (NFTs) which is pathological hallmarks of Alzheimer’s disease (AD) is composed of highly phosphorylated tau protein. Accumulation of biometals including Zn2+ and Cu2+ in NFTs promotes phosphorylation and aggregation of tau. Clioquinol (CQ) is a biometal chelator that passes through the blood brain barrier. The effects of CQ on tau phosphorylation and oligomer formation were examined in neuroblastoma cell line expressing wild-type tau (4R0N) via Tetracycline off induction. Two uM of CQ significantly reduced Cu+ in tau-expressing cells. Cu+ in tau-expressing cells was significantly reduced. Furthermore, CQ decreased phosphorylated tau via inactivating tau kinases, NK and P38MAP kinase. CQ decreased oligomeric tau by activating proteasomes and autophagy. Biometal chelator, such as CQ can be the therapeutic target of AD.

Academic Significance and Societal Importance of the Research Achievements

バイオメタルキレート薬　クリオキノールは細胞内のCu+を減少させた。また10μM以下であれば細胞毒性を示すことはなかった。さらに、タウリン酸化酵素を阻害することによるリン酸化タウの減少、ならびにオートファジー・プロテアソームを活性化し、重合した分子を含むタウを減少させることが明らかとなった。剖検脳でのバイオメタルの確認やマウスを用いた検討を行った後に、臨床研究を介して臨床応用するなどトランスレーショナルリサーチに応用できる可能性があり、今後の発展性が期待される。

Research Products

• [Int'l Joint Research] Mayo Clinic Jacksonville/Michigan State Unviersity(米国)
• [Int'l Joint Research] 浙江省人民医院/浙江省立同徳医院(中国)
• [Int'l Joint Research] Mayo Clinic Jacksonville/Michigan State University(米国)
• [Int'l Joint Research] Zhejiang Provincial People's Hospital/Tongde Hospital of Zhejiang Province(中国)
• [Int'l Joint Research] Mayo Clinic Jacksonville/Michigan State University(米国)
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• [Journal Article] Development of a Novel Nutrition-Related Multivariate Biomarker for Mild Cognitive Impairment Based on the Plasma Free Amino Acid Profile. (2022)
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• [Journal Article] Influences of Vitamin B12 Supplementation on Cognition and Homocysteine in Patients with Vitamin B12 Deficiency and Cognitive Impairment. (2022)
  • Author(s): Ueno A, Hamano T, Enomoto S, Shirafuji N, Nagata M, Kimura H, Ikawa M, Yamamura O, Yamanaka D, Ito T, Kimura Y, Kuriyama M, Nakamoto Y.
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• [Journal Article] Rho-ROCK阻害薬によるタウ蛋白オリゴマー形成抑制 (2022)
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• [Journal Article] Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM)-like Symptoms Associated with Anti-ganglionic Acetylcholine Receptor Antibodies (2021)
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• [Journal Article] Autophagy and Tau Protein. (2021)
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• [Journal Article] Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein. (2021)
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• [Journal Article] Clinicopathologic Features of Oculopharyngodistal Myopathy With LRP12 CGG Repeat Expansions Compared With Other Oculopharyngodistal Myopathy Subtypes. (2021)
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  • Journal Title: JAMA Neurol. Volume: 78(7) Issue: 7 Pages: 853-853
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• [Journal Article] Development of a Scoring System to Predict Prolonged Post-Stroke Dysphagia Remaining at Discharge from a Subacute Care Hospital to the Home. (2021)
  • Author(s): Ito Y, Goto T, Huh JY, Yamamura O, Hamano T, Kikuta KI, Hayashi H.
  • Journal Title: J Stroke Cerebrovasc Dis. Volume: 30(7) Issue: 7 Pages: 105804-105804
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• [Journal Article] オートファジーとタウオパチー． (2021)
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  • Journal Title: 脳神経内科 Volume: 95(4) Pages: 448-457
• [Journal Article] タウ蛋白とオートファジー. (2021)
  • Author(s): 濱野忠則，浅野礼，佐々木宏仁、山口智久，北﨑佑樹，遠藤芳徳，濱由香，白藤法道、 中本安成.
  • Journal Title: 細胞 Volume: 53 Pages: 781-787
  • NAID: 40022470680
• [Journal Article] Tau蛋白とオートファジー (2021)
  • Author(s): 濱野忠則、白藤 法道, 佐々木 宏仁, 山口 智久, 遠藤 芳徳, 武藤 多津郎, 中本 安成 Source： 細胞 (1346-7557) Page44-46(2021.01) 抄録を見る 所蔵確認
  • Journal Title: 細胞 Volume: 53巻1号 Pages: 44-46
• [Journal Article] 症例報告 脳脊髄液中のJCV-DNA遺伝子検査が2回とも陰性であったが,開頭脳生検で診断確定したHIV関連進行性多巣性白質脳症の1例 (2020)
  • Author(s): Kitazaki Y, Iwasaki H, Kitai R, Takahashi K, Nakamichi K, Hamano T.
  • Journal Title: BRAIN and NERVE Volume: 72 Issue: 5 Pages: 541-546
  • DOI: 10.11477/mf.1416201559
  • NAID: 40022256118
  • ISSN: 1344-8129, 1881-6096
  • Year and Date: 2020-05-01
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• [Journal Article] Statin Intolerance Clinical Guide 2018 (2020)
  • Author(s): Kajinami K, Tsukamoto K, Koba S, Inoue I, Yamakawa M, Suzuki S, Hamano T, Saito H, Saito Y, Masuda S, Nakayama T, Okamura T, Yamashita S, Kagawa T, Kaneyama J, Kuriyama A, Tanaka R, Hirata A: Statin Intolerance Clinical Guide Working Group
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 27 Issue: 4 Pages: 375-396
  • DOI: 10.5551/jat.50948
  • NAID: 130007824993
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  • Year and Date: 2020-04-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autoimmune Encephalitis Associated with Anti-gamma-aminobutyric Acid B Receptor Antibodies Mimicking Syncope (2020)
  • Author(s): Kitazaki Y, Ikawa M, Yamaguchi T, Enomoto S, Kishitani T, Shirafuji N, Hayashi K, Yamamura O, Nakamoto Y, Hamano T
  • Journal Title: Internal Medicine Volume: 59 Issue: 6 Pages: 843-847
  • DOI: 10.2169/internalmedicine.3652-19
  • NAID: 130007808724
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-03-15
  • Peer Reviewed / Open Access
• [Journal Article] Influences of Folate Supplementation on Homocysteine and Cognition in Patients with Folate Deficiency and Cognitive Impairment. (2020)
  • Author(s): Hama Y, Hamano T, Shirafuji N, Hayashi K, Ueno A, Enomoto S, Nagata M, Kimura H, Matsunaga A, Ikawa M, Yamamura O, Ito T, Kimura Y, Kuriyama M, Nakamoto Y.
  • Journal Title: Nutrients. Volume: 12(10): Issue: 10 Pages: 3138-3138
  • DOI: 10.3390/nu12103138
  • Peer Reviewed / Open Access
• [Journal Article] Rho-kinase ROCK inhibitors reduce oligomeric tau protein (2020)
  • Author(s): Hamano T, Shirafuji N, Yen SH, Yoshida H, Kanaan NM, Hayashi K, Ikawa M, Yamamura O, Fujita Y, Kuruyama M, Nakamoto Y
  • Journal Title: Neurobiology of Aging Volume: 89 Pages: 41-54
  • DOI: 10.1016/j.neurobiolaging.2019.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diffusion-weighted magnetic resonance imaging in dura mater graft-associated Creutzfeldt-Jakob disease (2020)
  • Author(s): Sakai Kenji、Hamaguchi Tsuyoshi、Sanjo Nobuo、Murai Hiroyuki、Iwasaki Yasushi、Hamano Tadanori、Honma Mari、Noguchi-Shinohara Moeko、Nozaki Ichiro、Nakamura Yosikazu、Kitamoto Tetsuyuki、Harada Masafumi、Mizusawa Hidehiro、Yamada Masahito
  • Journal Title: Journal of the Neurological Sciences Volume: 418 Pages: 117094-117094
  • DOI: 10.1016/j.jns.2020.117094
  • Peer Reviewed
• [Journal Article] A case of longitudinally extensive transverse myelitis with an isolated pontine lesion following epidural and spinal anesthesia for cesarean section. (2020)
  • Author(s): Kitazaki Y, Ueno A, Maeda K, Asano R, Satomi H, Nishio T, Nakamoto Y, Hamano T.
  • Journal Title: eNeurologicalSci. Volume: 21 Pages: 100264-100264
  • DOI: 10.1016/j.ensci.2020.100264
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• [Journal Article] An autopsy case of tuberculous meningitis undiagnosed by nested-PCR of CSF samples and brain biopsy. (2020)
  • Author(s): Kitazaki Y, Ikawa M, Enomoto S, Shirafuji N, Hayashi K, Yamamura O, Yamada S, Arishima H, Noriki S, Nakamoto Y, Hamano T.
  • Journal Title: J Neurol Sci. Volume: 415 Pages: 116968-116968
  • DOI: 10.1016/j.jns.2020.116968
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• [Journal Article] A case of asymptomatic Stanford type A aortic dissection with multiple perforator infarcts due to pseudointracavitary thrombus (2020)
  • Author(s): Kitazaki Y, Asano R, Hayashi K, Yamamura O, Tanabe S, Hamano T.
  • Journal Title: Rinsho Shinkeigaku Volume: 60 Issue: 12 Pages: 874-877
  • DOI: 10.5692/clinicalneurol.cn-001474
  • NAID: 130007961922
  • ISSN: 0009-918X, 1882-0654
  • Peer Reviewed
• [Journal Article] A case of post-surgical inflammatory neuropathy with lower-extremity weakness after surgery for anorectal malignant melanoma that showed the effectiveness of immunotherapy (2020)
  • Author(s): Asano R, Kitazaki Y, Ikawa M, Kurebayasi H, Koike H, Hamano T.
  • Journal Title: Rinsho Shinkeigaku Volume: 60 Issue: 11 Pages: 762-767
  • DOI: 10.5692/clinicalneurol.cn-001441
  • NAID: 130007945146
  • ISSN: 0009-918X, 1882-0654
  • Peer Reviewed
• [Journal Article] A case of neuromyelitis optica spectrum disorder with persistent nausea and repeated syncope (2020)
  • Author(s): Endo Y, Hayashi K, Ikawa M, Yamamura O, Ookura K, Hamano T.
  • Journal Title: Rinsho Shinkeigaku Volume: 60 Issue: 2 Pages: 142-145
  • DOI: 10.5692/clinicalneurol.cn-001345
  • NAID: 130007802649
  • ISSN: 0009-918X, 1882-0654
  • Peer Reviewed
• [Journal Article] Localized Right Subclavian Artery Dissection Detected by Accident on an Ultrasound Examination: A Case Report and Literature Review (2019)
  • Author(s): Onishi H, Yamamura O, Matsuo S, Tanaka T, Daitoku S, Konokawa S, Tsubouchi H, Chiba H, Sone M, Kaku B, Enomoto S, Yamamoto T, Hashimoto Y, Hamano T, Hayashi H,
  • Journal Title: Internal Medicine Volume: 58 Issue: 1 Pages: 73-78
  • DOI: 10.2169/internalmedicine.1451-18
  • NAID: 130007542248
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-01-01
  • Peer Reviewed / Open Access
• [Journal Article] Subventricular glial nodules in neurofibromatosis 1 with craniofacial dysmorphism and occipital meningoencephalocele (2019)
  • Author(s): Hamano Tadanori、Mutoh Tatsuro、Naiki Hironobu、Shirafuji Norimichi、Ikawa Masamichi、Yamamura Osamu、Dickson Dennis W.、Aiki Shichiryoemon、Kuriyama Masaru、Nakamoto Yasunari
  • Journal Title: eNeurologicalSci Volume: 17 Pages: 100213-100213
  • DOI: 10.1016/j.ensci.2019.100213
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serial brain MRI changes related to autoimmunepathophysiology in Hashimoto encephalopathy with anti-NAE antibodies: A case-series study. (2019)
  • Author(s): Matsunaga A, Ikawa M, Kawamura Y, Kishitani T, Yamamura O, Hamano T, Kimura H,
  • Journal Title: J Neurol Sci. Volume: 406 Pages: 116453-116453
  • DOI: 10.1016/j.jns.2019.116453
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• [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
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• [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
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• [Presentation] Lithium chloride inhibits phosphorylation of tau protein. (2021)
  • Author(s): Asano, R., Hamano, T., Yen, S. H., Sasaki, H., Yamaguchi, T., Endo, Y., ... & Nakamoto, Y.
  • Organizer: Alzheimer Association International Conference (AAIC)2021
  • Int'l Joint Research
• [Presentation] 認知症の診断と治療 ―早期介入を目指してー (2021)
  • Author(s): 濵野忠則
  • Organizer: 日本内科学会北陸地方会 第83回生涯教育講演会
  • Invited
• [Presentation] Clioquinol reduces tau phosphorylation and oligomerization: Molecular and cell biology/tau. (2020)
  • Author(s): Zhu, F., Lin, G., Hamano, T., Kanaan, N. M., Yen, S. H., Asano, R. Nakamoto, Y.
  • Organizer: Alzheimer's Association International Conference (AAIC) 2020
  • Int'l Joint Research
• [Presentation] Syk inhibitor reduces oligomeric tau associated with GSK3β inactivation and autophagy activation (2020)
  • Author(s): Yamaguchi, T., Hamano, T., Sada, K., Kanaan, N. M., Sasaki, H., Yen, S. H., ... & Nakamoto, Y. (2020).
  • Organizer: Alzheimer's Association International Conference (AAIC) 2020
  • Int'l Joint Research
• [Presentation] VITAMIN B12 SUPPLEMENTATION IMPROVES HYPERHOMOCYSTEINEMIA AND COGNITIVE IMPAIRMENT IN PATIENTS WITH VITAMIN B12 DEFICIENCY. (2019)
  • Author(s): Ueno, A., Hamano, T., Enomoto, S., Shirafuji, N., Nagata, M., Yamaguchi, T., Kuriyama, M.
  • Organizer: AAIC2019 Alzhimer's Association of International Conference2019 in Los Angeles.
  • Int'l Joint Research
• [Presentation] ALPHA-SYNUCLEIN PHOSPHORYLATION BY HOMOCYSTEINE. (2019)
  • Author(s): Enomoto, S., Hamano, T., Jiang, P., Shirafuji, N., Sasaki, H., et al.
  • Organizer: AAIC2019 Alzhimer's Association of International Conference2019 in Los Angeles
  • Int'l Joint Research
• [Book] 最新主要文献とガイドラインでみる脳神経内科学レビュー2022-23 (2022)
  • Author(s): 濵野忠則
  • Total Pages: 433
  • Publisher: 総合医学社
• [Book] 認知症診療 実践ハンドブック 第二版 (2021)
  • Author(s): 濵野忠則
  • Total Pages: 439
  • Publisher: 中外医学社
• [Book] 認知症診療実践ハンドブック 改訂2版 3 抗認知症薬による治療 (2021)
  • Author(s): 濱野忠則
  • Total Pages: 439
  • Publisher: 中外医学社
  • ISBN: 9784498228931
• [Book] 認知症診療実践ハンドブック 改訂2版 9 若年性認知症を支える (2021)
  • Author(s): 濱野忠則
  • Total Pages: 439
  • Publisher: 中外医学社
  • ISBN: 9784498228931
• [Book] 認知症診療実践ハンドブック 改訂2版 12 内分泌・代謝・栄養欠乏性疾患 (2021)
  • Author(s): 林 浩嗣、濱野忠則
  • Total Pages: 439
  • Publisher: 中外医学社
  • ISBN: 9784498228931
• [Book] 今日の診断指針 第8版 (2020)
  • Author(s): 濱野忠則
  • Total Pages: 2079
  • Publisher: 医学書院
  • ISBN: 9784260038089
• [Patent(Industrial Property Rights)] ROCK阻害剤およびSyk阻害剤の利用 (2020)
  • Inventor(s): 濱野忠則
  • Industrial Property Rights Holder: 濱野忠則
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Overseas