Regulation of oxidative stress in Alzheimer model mice and its application for treatment

• Project/Area Number: 16H05279
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Sapporo Medical University
• Principal Investigator: Shimohama Shun 札幌医科大学, 医学部, 教授 (60235687)
• Co-Investigator(Renkei-kenkyūsha): Fujii Hirotada 札幌医科大学, 医療人育成センター, 教授 (70209013)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: アルツハイマー病 / 酸化ストレス / βアミロイド / ミクログリア / α7ニコチン性受容体作動薬 / ガランタミン / 骨髄間葉系幹細胞 / 治療・予防薬 / モデルマウス / アミロイドβ / 治療 / EPR / ニコチン受容体 / 脳神経疾患 / 電子常磁性共鳴法

Outline of Final Research Achievements

It is recognized that increased oxidative damage on neurons is an early event in Alzheimer's disease (AD). Galantamine is one of acetylcholinesterase inhibitors and has an allosteric potentiating ligand function for nicotinic acetylcholine receptors. We showed that earlier treatment (before the appearance of Aβ plaques) of galantamine results in the improvement of cognitive function and suppresses the oxidative stress and the progression of pathological findings in AD mice. Bone marrow mesenchymal stem cell (BMSC)-treatment improved spatial memory impairment and reduced Aβ plaques deposition and Aβ1-42 levels of soluble fraction of brain homogenates in AD mice. The oxidative stress in the BMSC-treated mouse brain were also ameliorated. These findings suggest that galantamine and BMSC may prevent the progression of AD pathology by controlling oxidative stress and excessive Aβ deposition.

Academic Significance and Societal Importance of the Research Achievements

急激に高齢化が進む中で，費用対効果に優れたADに対する治療方法の確立が急務である。ガランタミンはすでにAD治療薬として使用されているため、安全性という面でも確立されている薬剤であり、費用対効果に優れた予防薬となる可能性がある。骨髄間葉系幹細胞は他疾患ですでに実臨床応用が開始されている治療であり安全性の検討がなされていることから、詳細な分子生物学的機序を解明することができれば、ADに対する新規治療として近い将来に実現可能であると考えられる。

Research Products

• [Journal Article] Eculizumab improves fatigue in refractory generalized myasthenia gravis. (2019)
  • Author(s): Andersen H, Mantegazza R, Wang JJ, O'Brien F, Patra K, Howard JF Jr; REGAIN Study Group.
  • Journal Title: Qual Life Res. Volume: - Issue: 8 Pages: 2247-2254
  • DOI: 10.1007/s11136-019-02148-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinical and Radiological Characteristics of Intracranial Artery Dissection Using Recently Proposed Diagnostic Criteria (2019)
  • Author(s): Nakamura Y, Yamaguchi Y, Makita N, Morita Y, Ide T, Wada S, Mizoguchi T, Ikenouchi H, Miwa K, Yi K, Irie K, Shimohama S, Ihara M, Toyoda K, Koga M
  • Journal Title: J Stroke Cerebrovasc Dis Volume: Epub Issue: 6 Pages: 30063-1
  • DOI: 10.1016/j.jstrokecerebrovasdis.2019.02.019
  • Peer Reviewed
• [Journal Article] CD14 and Toll-Like Receptor 4 Promote Fibrillar Aβ42 Uptake by Microglia Through A Clathrin-Mediated Pathway. (2019)
  • Author(s): Fujikura M, Iwahara N, Hisahara S, Kawamata J, Matsumura A, Yokokawa K, Saito T, Manabe T, Matsushita T, Suzuki S, Shimohama S.
  • Journal Title: J Alzheimers Dis. Volume: 68 Issue: 1 Pages: 323-337
  • DOI: 10.3233/jad-180904
  • Peer Reviewed
• [Journal Article] Long-term safety and efficacy of eculizumab in generalized myasthenia gravis. (2019)
  • Author(s): Muppidi S, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, Jacob S, Vissing J, Burns TM, Kissel JT, Nowak RJ, Andersen H, Casasnovas C, de Bleecker JL, Vu TH, Mantegazza R, O'Brien FL, Wang JJ, Fujita KP, Howard JF Jr; Regain
  • Journal Title: Muscle Nerve. Volume: - Issue: 1 Pages: 14-24
  • DOI: 10.1002/mus.26447
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of Mitochondrial Oxidative Stress in the Brain of a Transgenic Mouse Model of Alzheimer's Disease by in vitro Electron Paramagnetic Resonance Spectroscopy. (2019)
  • Author(s): Manabe T, Matsumura A, Yokokawa K, Saito T, Fujikura M, Iwahara N, Matsushita T, Suzuki S, Hisahara S, Kawamata J, Suzuki H, Emoto MC, Fujii HG, Shimohama S.
  • Journal Title: Journal of Alzheimer's disease Volume: 67 Issue: 3 Pages: 1079-1087
  • DOI: 10.3233/jad-180985
  • Peer Reviewed
• [Journal Article] The Japanese early-stage trial of high-dose methylcobalamin for amyotrophic lateral sclerosis (JETALS): Protocol for a randomized controlled trial (2018)
  • Author(s): Oki Ryosuke、Izumi Yuishin、Nodera Hiroyuki、Ishihara Tomohiko，Kaji Ryuji、JETALS et al.
  • Journal Title: JMIR Research Protocols Volume: 7 Issue: 12 Pages: e12046-e12046
  • DOI: 10.2196/12046
  • Peer Reviewed / Open Access
• [Journal Article] Development of moyamoya disease after non-herpetic acute limbic encephalitis: A case report. (2018)
  • Author(s): Takahashi Y, Mikami T, Suzuki H, Komatsu K, Yamamoto D, Shimohama S, Houkin K, Sugita S, Hasegawa T, Mikuni N.
  • Journal Title: J Clin Neurosci. Volume: 53 Pages: 250-253
  • DOI: 10.1016/j.jocn.2018.04.042
  • Peer Reviewed
• [Journal Article] Establishing a New Screening System for Mild Cognitive Impairment and Alzheimer's Disease with Mental Rotation Tasks that Evaluate Visuospatial Function. (2018)
  • Author(s): Suzuki A, Shinozaki J, Yazawa S, Ueki Y, Matsukawa N, Shimohama S, Nagamine T.
  • Journal Title: J Alzheimers Dis Volume: 61(4) Issue: 4 Pages: 1653-1665
  • DOI: 10.3233/jad-170801
  • Peer Reviewed
• [Journal Article] Alpha7 nicotinic acetylcholine receptor-specific agonist DMXBA (GTS-21) attenuates Aβ accumulation through suppression of neuronal γ-secretase activity and promotion of microglial amyloid-β phagocytosis and ameliorates cognitive impairment in a mouse model of Alzheimer's disease. (2018)
  • Author(s): Takata K., et al.
  • Journal Title: Neurobiol Aging Volume: 62 Pages: 197-209
  • DOI: 10.1016/j.neurobiolaging.2017.10.021
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis (2018)
  • Author(s): Miyazaki Yusei、Niino Masaaki、Takahashi Eri、Suzuki Masako、Mizuno Masanori、Hisahara Shin、Fukazawa Toshiyuki、Amino Itaru、Nakano Fumihito、Nakamura Masakazu、Akimoto Sachiko、Minami Naoya、Fujiki Naoto、Doi Shizuki、Shimohama Shun、Terayama Yasuo、Kikuchi Seiji
  • Journal Title: Clinical Immunology Volume: 187 Pages: 95-101
  • DOI: 10.1016/j.clim.2017.10.009
  • Peer Reviewed
• [Journal Article] Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice. (2017)
  • Author(s): Iwahara N, Hisahara S, Kawamata J, Matsumura A, Yokokawa K, Saito T, Fujikura M, Manabe T, Suzuki H, Matsushita T, Suzuki S, Shimohama S.
  • Journal Title: J Alzheimers Dis. Volume: 55 Issue: 3 Pages: 1235-1247
  • DOI: 10.3233/jad-160887
  • Peer Reviewed
• [Journal Article] Effects of a DJ-1-binding compound on spatial learning and memory impairment in a mouse model of Alzheimer's disease (2017)
  • Author(s): Kitamura Y, Inden M, Kimoto K, Takata K, Yanagisawa D, Hijioka M, Ashihara K, Tooyama I, Shimohama S, Ariga H
  • Journal Title: Journal of Alzheimer’s Disease Volume: 55 Issue: 1 Pages: 67-72
  • DOI: 10.3233/jad-160574
  • Peer Reviewed
• [Journal Article] Role of suppressor of cytokine signaling 3 (SOCS3) in altering activated microglia phenotype in APPswe/PS1dE9 mice (2017)
  • Author(s): Iwahara n, Hisahara S, Kawamata J, Matsumura A, Yokokawa K, Saito T, Fujikura M, Manabe T, Suzuki H, Matsushita T, Suzuki S, Shimohama S
  • Journal Title: Journal of Alzheimers Disease Volume: 55 Pages: 1235-1247
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of a DJ-1-binding compound on spatial learning and memory impairment in a mouse model of Alzheimer disease (2017)
  • Author(s): Kitamura Y, Inden M, Kimoto Y, Takata K, Yanagisawa D, Hijioka M, Ashihara E, Tooyama I, Shimohama S, Ariga H
  • Journal Title: Journal of Alzheimers Disease Volume: 55 Pages: 67-72
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Progressive multifocal leukoencephalopathy after autologous peripheral blood stem cell transplantation in a patient with multiple myeloma treated with combination therapy (2016)
  • Author(s): Yokokawa K, Hisahara S, Matsuura Y, Ikeda K, Tsuda E, Saitoh M, Nakamichi K, Saijo M, Kamihara Y, Sato T, Kawamata J, Shimohama S
  • Journal Title: Journal of Neurological Science Volume: 368 Pages: 304-306
  • DOI: 10.1016/j.jns.2016.07.045
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Inhibition of monocarboxylate transporter 1 suppresses the proliferation of glioblastoma stem cells. (2016)
  • Author(s): Takada T, Takata K, Ashihara E.
  • Journal Title: J Physiol Sci Volume: 66 Pages: 74-81
  • DOI: 10.1016/j.neuint.2016.02.008
  • NAID: 40020922534
  • Peer Reviewed / Open Access
• [Presentation] Temporal changes of CD14 expression in APdE9 mice. (2018)
  • Author(s): Fujikura M, Shimohama S, et al.
  • Organizer: 59th Annual Meeting of the Japanese Society of Neurology
• [Presentation] Rat Bone Marrow-derived MSC Improve Oxidative Stress in Alzheimer's Disease Mouse Mode. (2018)
  • Author(s): Yokokawa K, Shimohama S, et al.
  • Organizer: 59th Annual Meeting of the Japanese Society of Neurology
• [Presentation] Effectiveness of galantamine treatment in normal cognition phase of APPswe/PS1dE9 mice.. (2018)
  • Author(s): Saito T, Shimohama S, et al.
  • Organizer: 59th Annual Meeting of the Japanese Society of Neurology
• [Presentation] The evaluation of mitochondrial Abeta accumulation and oxidative stress in APdE9 mice (2018)
  • Author(s): Manabe T, Shimohama S, et al.
  • Organizer: 59th Annual Meeting of the Japanese Society of Neurology
• [Presentation] CD14 and Toll-like receptor 4 promote fibrillar Aβ uptake by microglia through clathrin-mediated pathway. (2018)
  • Author(s): Fujikura M, Shimohama S, et al.
  • Organizer: 37th Annual Meeting of Japanese Society for Dementia Research
• [Presentation] APPswe/PS1dE9マウスにおけるガランタミンの超早期治療の有効性. (2018)
  • Author(s): 齋藤太郎，下濱俊ら.
  • Organizer: 37th Annual Meeting of Japanese Society for Dementia Research
• [Presentation] アルツハイマー病モデルマウスでは早期にミトコンドリアで酸化ストレスが増大する. (2018)
  • Author(s): 真部達郎，下濱俊ら.
  • Organizer: 37th Annual Meeting of Japanese Society for Dementia Research
• [Presentation] アルツハイマー病モデルマウスにおける骨髄間葉系幹細胞治療のメカニズム検討. (2018)
  • Author(s): 横川和樹，下濱俊ら.
  • Organizer: 37th Annual Meeting of Japanese Society for Dementia Research
• [Presentation] 脳血流IMP-SPECTにおけるCIScore解析によるDLB・AD鑑別の検証. (2018)
  • Author(s): 松村晃寛，下濱俊ら.
  • Organizer: 37th Annual Meeting of Japanese Society for Dementia Research
• [Presentation] Stimulation of nicotinic acetylcholine receptor suppresses expression of CD14 in microglia. (2017)
  • Author(s): Fujikura M, Shimohama S, et al.
  • Organizer: The XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Cytosolic SIRT3 Protects PC12 cells against amyloid beta toxicity. (2017)
  • Author(s): Matsushita T, Shimohama S, et al.
  • Organizer: The XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Transplantation of Rat bone marrow-derived mesenchymal stem cells regulates oxidative stress in alzheimer’s disease transgenic mouse model. (2017)
  • Author(s): Yokokawa K, Shimohama S, et al.
  • Organizer: The XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Efficacy of galantamine treatment in very early stage of APPSWE/PS1DE9 mice. (2017)
  • Author(s): Saito T, Shimohama S, et al.
  • Organizer: The XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Early Aβ accumulation in the mitochondria produces oxidative stress and Induces neurodegeneration in APDE9 mice. (2017)
  • Author(s): Manabe T, Shimohama S, et al.
  • Organizer: The XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Mesenchymal stem cell-conditioned medium induces microglia into M2 phenotype and promotes amyloid β-phagocytosis. (2017)
  • Author(s): Iwahara N, Saito T, et al.
  • Organizer: The XXIII World Congress of Neurology
  • Int'l Joint Research
• [Book] Nicotinic Acetylcholine Receptor Signaling in Neuroprotection (2018)
  • Author(s): Akaike A, Shimohama S, Misu Y
  • Total Pages: 191
  • Publisher: Springer
  • ISBN: 9789811084874