Molecular mechanisms of Alzheimer's disease induced by oligomeric tau protein.

• Project/Area Number: 25460893
• 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, 医学部, 准教授 (40334817)
• Co-Investigator(Kenkyū-buntansha): Naiki Hironobu 福井大学, 医学部, 教授 (10227704) ; Shirafuji Norimichi 福井大学, 医学部附属病院, 医員 (40529319)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: アルツハイマー病 / タウ蛋白 / タウオリゴマー / 神経細胞死 / ピオグリタゾン / オリゴマー / GSK3β

Outline of Final Research Achievements

One of the pathological hallmarks of Alzheimer’s disease (AD) is neurofibrillary tangle (NFT) which is composed of highly phosphorylated tau protein. It was shown that oligomeric tau causes neuronal cell death. We have demonstrated that neuronal cell models which express the wild type tau protein via TET OFF induction shows 120 kDa, 180 kDa, and 240 kDa oligomeric tau in sarkosyl insoluble fraction which was shown by Western blotting. It was also shown that oligomeric tau activates caspase3, and induces neuronal cell death. We have also determined that pioglitazone, PPARgamma agonist, decreased phosphorylated tau, as well as oligomeric tau.

Research Products

• [Int'l Joint Research] Mayo Clinic Jacksonville/Michigan State Ｕｎｉｖｅｒｓｉｔｙ(米国)
• [Int'l Joint Research] Zhejiang provincial people’s Hospital(中国)
• [Journal Article] Molecular pathogenesis ofhuman amyloidosis: Lessons from β2 -microglobulin-related amyloidosis. (2016)
  • Author(s): Naiki H, Okoshi T, Ozawa D, Yamaguchi I, Hasegawa K.
  • Journal Title: Pathol Int. Volume: ;66(4) Issue: 4 Pages: 193-201
  • DOI: 10.1111/pin.12394
  • Peer Reviewed / Open Access
• [Journal Article] Increased oxidative stress is related to disease severity in the ALS motor cortex: A PET study. (2015)
  • Author(s): Ikawa M, Okazawa H, Tsujikawa T, Matsunaga A, Yamamura O, Mori T, Hamano T,
  • Journal Title: Neurology Volume: 84 Issue: 20 Pages: 1-8
  • DOI: 10.1212/wnl.0000000000001588
  • Peer Reviewed
• [Journal Article] C-terminal sequence of amyloid-resistant type F apolipoprotein A-II inhibits amyloid fibril formation of apolipoprotein A-II in mice. (2015)
  • Author(s): J.Sawashita, B.Zhang, K.Hasegawa, M.Mori, H.Naiki, F.Kametani, K.Higuchi.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 112 Issue: 8
  • DOI: 10.1073/pnas.1416363112
  • Peer Reviewed / Open Access
• [Journal Article] Endocytosed β2-Microglobulin Amyloid Fibrils Induce Necrosis and Apoptosis of Rabbit Synovial Fibroblasts by Disrupting Endosomal/Lysosomal Membranes: A Novel Mechanism on the Cytotoxicity of Amyloid Fibrils. (2015)
  • Author(s): Okoshi T, Yamaguchi I, Ozawa D, Hasegawa K, Naiki H
  • Journal Title: PLoS One Volume: 10 Issue: 9 Pages: e0139330-e0139330
  • DOI: 10.1371/journal.pone.0139330
  • Peer Reviewed / Open Access
• [Journal Article] Pathophysiological Decrease in the Regional Cerebral Blood Flow in Hashimoto’s Encephalopathy: A Multiple-Case SPECT Study. (2014)
  • Author(s): Tomoko Muramatsu, Masamichi Ikawa, Makoto Yoneda, Katsuya Sugimoto, Akiko Matsunaga, Osamu Yamamura., Tadanori Hamano, Hidehiko Okazawa, Yasunari Nakamoto
  • Journal Title: Eur Neurol Volume: 72 Issue: 1-2 Pages: 13-19
  • DOI: 10.1159/000358220
  • Peer Reviewed
• [Journal Article] A case of left hemi-facial metamorphopsia induced by infarction of the right side of thesplenium of the corpus callosum (2014)
  • Author(s): Saito Y, Matsunaga A, Yamamura O, Ikawa M, Hamano T, Yoneda M.
  • Journal Title: Rinsho Shinkeigaku Volume: 54(8) Pages: 637-642
  • Peer Reviewed
• [Journal Article] Case of interval form of carbon monoxide poisoning without increased carboxyhemoglobin level diagnosed by characteristic MR spectroscopy findings. (2014)
  • Author(s): Kamisawa T, Ikawa M, Hamano T, Nagata M, Kimura H, Yoneda M
  • Journal Title: Rinsho Shinkeigaku Volume: 54(3) Pages: 234-7
  • NAID: 130004505574
  • Peer Reviewed
• [Journal Article] アルツハイマー病とホモシステイン (2014)
  • Author(s): 濱野忠則、白藤法道、栗山 勝、中本安成
  • Journal Title: ビタミン Volume: ８８（２） Pages: 92-96
  • Peer Reviewed
• [Journal Article] 医薬品副作用、中毒性疾患 医薬品による神経・筋骨格系障害 横紋筋融解症 (2014)
  • Author(s): 濱野忠則
  • Journal Title: 日本臨床 Volume: 別冊症候群V Pages: 598-602
• [Journal Article] 良性一側下腿筋萎縮症(BMALL) (2014)
  • Author(s): 濱野忠則
  • Journal Title: 日本臨床 Volume: 別冊神経症候群II Pages: 556-559
• [Journal Article] Pathophysiological Decrease in the Regional Cerebral Blood Flow in Hashimoto's Encephalopathy: A Multiple-Case SPECT Study. (2014)
  • Author(s): Muramatsu T, Ikawa M, Yoneda M, Sugimoto K, Matsunaga A, Yamamura O, Hamano T,Okazawa H, Nakamoto Y
  • Journal Title: Eur Neurol Volume: 72(1-2):13-19. Pages: 13-19
  • Peer Reviewed
• [Journal Article] A case of interval form of carbon monoxide poisoning without increased carboxyhemoglobinlevel diagnosed by characteristic MR spectroscopy findings. (2014)
  • Author(s): Kamisawa T, Ikawa M, Hamano T, Nagata M, Kimura H, Yoneda M.
  • Journal Title: Rinsho Shinkeigaku. Volume: 54 Pages: 234-237
  • NAID: 130004505574
  • Peer Reviewed
• [Journal Article] 良性一側下腿筋萎縮症(BMALL) (2014)
  • Author(s): 濱野忠則
  • Journal Title: 日本臨床(0047-1852)別冊神経症候群II神経症候群(第2版)- Volume: 27 Pages: 556-559
• [Journal Article] アルツハイマー病とホモシステイン (2014)
  • Author(s): 濱野 忠則, 白藤 法道, 栗山 勝, 中本 安成
  • Journal Title: ビタミン Volume: 88巻2号 Pages: 92-96
  • Peer Reviewed
• [Journal Article] Detection of preclinically latent hyperperfusion due to stroke-like episodes by arterial spin-labeling perfusion MRI in MELAS patients. (2013)
  • Author(s): Masamichi Ikawa, Makoto Yoneda, Tomoko Muramatsu, Akiko Matsunaga, Tetsuya Tsujikawa, Tatsuya Yamamoto, Nobuyuki Kosaka, Kazuyuki Kinoshita, Osamu Yamamura, Tadanori Hamano, Yasunari Nakamoto, Hirohiko Kimura
  • Journal Title: Mitochondrion Volume: 13(6) Issue: 6 Pages: 676-680
  • DOI: 10.1016/j.mito.2013.09.007
  • Peer Reviewed
• [Journal Article] Hashimoto's encephalopathy presenting periodic synchronous discharge, as a differential diagnosis for Creutzfeldt-Jakob disease. (2013)
  • Author(s): Muramatsu T, Hamano T, Shirafuji N, Matsunaga A, Ikawa M, Yoneda M.
  • Journal Title: Rinsho Shinkeigaku. Volume: 53 Pages: 716-720
  • NAID: 130004505551
  • Peer Reviewed
• [Journal Article] Medical cooperation using IT networks--From the medical care experience of a patient with terminal amyotrophic lateral sclerosis (ALS) (2013)
  • Author(s): Yamamura O, Nakachi R, Ikawa M, Hamano T, Yoneda M, Yamashita Y.
  • Journal Title: Rinsho Shinkeigaku Volume: 53 Pages: 29-32
  • NAID: 130004505299
  • Peer Reviewed
• [Presentation] Efficacy of short questionnaire for screening of early stage of dementia (2016)
  • Author(s): Hamano T, Fujita Y, Matsubara R, Nagata M, Ikebata Y, Ito T, Endo Y, Ueno A, Shirafuji N, Hayashi K, Yamamura O, Nakamoto Y
  • Organizer: Alzheimer's Association International Conference AAIC2016
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2016-07-23
  • 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 AAIC2016
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2016-07-23
  • Int'l Joint Research
• [Presentation] Clioquinol Decreases Phosphorylation Leves of Tau Protein (2015)
  • Author(s): Lin K, Hamano T, Shirafuji N, Ishida A, Nakamoto Y
  • Organizer: Alzheimer Association International Conference AAIC 2015
  • Place of Presentation: Washington DC (USA)
  • Year and Date: 2015-07-18 – 2015-07-23
• [Presentation] Reduction of Serum Cholinesterase By Cholinesterase Inhibitor (Donepezil, Galantamine, or Rivastigmine) (2015)
  • Author(s): Hayashi K, Hamano T, Shirafuji N, Nakamoto Y
  • Organizer: Alzheimer Association International Conference AAIC 2015
  • Place of Presentation: Washington DC (USA)
  • Year and Date: 2015-07-18 – 2015-07-23
• [Presentation] Clioquinol decreases phosphorylation levels of tau protein. (2015)
  • Author(s): Lin G, Hamano T, Shirafuji N, Ishida A, Nakamoto Y
  • Organizer: Alzheimer's Association International Conference AAIC2015
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2015-07-18
  • Int'l Joint Research
• [Presentation] Reduction of cholineesterase by cholineesterase inhibitor (Donepezil, Galantamine, or Rivaastigmine). (2015)
  • Author(s): Hayashi K, Hamano T, SHirafuji N, Nakamoto Y
  • Organizer: Alzheimer's Association International Conference AAIC2015
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2015-07-18
  • Int'l Joint Research
• [Presentation] 若手医師のための「感染と免疫セミナー」ウイルス性髄膜炎・脳炎の診断と治療 (2014)
  • Author(s): 濱野忠則
  • Organizer: 第19回日本神経感染症学会総会学術集会
  • Place of Presentation: 金沢 歌劇座
  • Year and Date: 2014-09-04 – 2014-09-06
  • Invited
• [Presentation] ROCK INHIBITOR DECREASES PHOSPHORYLATION LEVELS OF TAU PROTEIN. (2014)
  • Author(s): Shirafuji, N., Hamano, T., Yen, S. H., Ishida, A., Fujita, Y., Matsunaga, A., ... & Nakamoto, Y.
  • Organizer: Alzheimer Association International Conference AAIC 2014
  • Place of Presentation: Copenhagen (Denmark)
  • Year and Date: 2014-07-12 – 2014-07-17
• [Presentation] CHRONIC CEREBRAL HYPOPERFUSION INDUCES TAU HYPERPHOSPHORYLATION ACCOMPANIED BY AXONAL DAMAGE IN ADULT MICE. (2014)
  • Author(s): Fujita, Y., Hamano, T., Shirafuji, N., & Nakamoto, Y.
  • Organizer: Alzheimer Association International Conference AAIC 2014
  • Place of Presentation: Copenhagen (Denmark)
  • Year and Date: 2014-07-12 – 2014-07-17
• [Presentation] ROCK inhibitor decreases phosphorylation levels of tau protein (2014)
  • Author(s): Hamano T, Shirafuji N, Yen SH, Ishida A, Fujita Y, Matsunaga A, Yamamura O, Kuriyama M, Nakamot Y
  • Organizer: Alzheimers Association International Conference 2014
  • Place of Presentation: Copenhagen, Denmark
• [Presentation] Homocysteine accelerates tau aggregation via caspase activation. (2013)
  • Author(s): Shirafuji, N., Hamano, T., Ishi-da, A., Yoneda, M., Kuriyama, M., Nakamoto, Y.
  • Organizer: Alzheimers Association International Conference 2013
  • Place of Presentation: Boston, USA
• [Presentation] Donepezil reduces phosphorylation levels of tau protein in a cellular model of tauopathy. (2013)
  • Author(s): Hamano, T., Shirafuji, N., Sasaki, H., Ishi-da, A., Ueno, A., Yen, S. H., Nakamoto, Y.
  • Organizer: Alzheimers Association International Conference 2013
  • Place of Presentation: Boston, USA