Analysis of oxidative stress in the brain in Alzheimer's disease model mice and establishment of bone marrow mesenchymal stem cell therapy

• Project/Area Number: 17K16388
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Psychiatric science
• Research Institution: Sapporo Medical University
• Principal Investigator: Yokokawa Kazuki 札幌医科大学, 医学部, 研究員 (30781273)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 間葉系幹細胞 / アルツハイマー病 / 認知症 / 酸化ストレス / ミクログリア / アミロイドβ / 骨髄間葉系幹細胞 / 電子常磁性共鳴 / 脳神経疾患

Outline of Final Research Achievements

Mesenchymal stem cells (MSC) has a therapeutic potential for Alzheimer's disease (AD) targeting various mechanisms including neuroprotective, immunomodulatory, and antioxidant action. The purpose of this study is to clarify the effect and treatment mechanism of MSC treatment on AD model mice. Transplantation of MSC ameliorated amyloid beta pathology in AD model mice through modifying amyloid beta clearance by microglia and improving the unbalanced redox status of the AD model mouse brain, thereby improving cognitive function.

Academic Significance and Societal Importance of the Research Achievements

札幌医科大学が中心となってすでに脳梗塞や脊髄損傷などの分野で自己骨髄間葉系幹細胞の経静脈的移植の臨床応用が開始されている。本研究ではアルツハイマー病に対する間葉系幹細胞による治療メカニズムの一端を明らかにすることができたと考えられ、将来のアルツハイマー病に対する病態抑制治療としての可能性を広げることができたと考えられる。

Research Products

• [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] 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] Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer's disease (2019)
  • Author(s): Saito Taro、Hisahara Shin、Iwahara Naotoshi、Emoto Miho C.、Yokokawa Kazuki、Suzuki Hiromi、Manabe Tatsuo、Matsumura Akihiro、Suzuki Syuuichirou、Matsushita Takashi、Kawamata Jun、Sato-Akaba Hideo、Fujii Hirotada G.、Shimohama Shun
  • Journal Title: Free Radical Biology and Medicine Volume: 145 Pages: 20-32
  • DOI: 10.1016/j.freeradbiomed.2019.09.014
  • Peer Reviewed
• [Journal Article] Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress (2019)
  • Author(s): Yokokawa Kazuki、Iwahara Naotoshi、Hisahara Shin、Emoto Miho C.、Saito Taro、Suzuki Hiromi、Manabe Tatsuo、Matsumura Akihiro、Matsushita Takashi、Suzuki Syuuichirou、Kawamata Jun、Sato-Akaba Hideo、Fujii Hirotada G.、Shimohama Shun
  • Journal Title: Journal of Alzheimer's Disease Volume: 72 Issue: 3 Pages: 867-884
  • DOI: 10.3233/jad-190817
  • Peer Reviewed / Open Access
• [Presentation] Rat Bone Marrow-derived MSCs Attenuate Oxidative Stress and Neuroinflammation in APP/PS1 mice. (2019)
  • Author(s): Kazuki Yokokawa, Naotoshi Iwahara, Miho C. Emoto, Shin Hisahara, Taro Saito, Mai Fujikura, Tatsuo Manabe, Takashi Matsushita, Akihiro Matsumura, Syuuichirou Suzuki, Jun Kawamata, Hirotada G. Fujii, Shun Shimohama
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] 骨髄間葉系幹細胞治療はミクログリアによる炎症応答を制御しAβ病理を改善する (2019)
  • Author(s): 横川和樹, 岩原直敏, 久原真, 齋藤太郎, 鈴木紘美, 松下隆司, 松村晃寛, 鈴木秀一郎, 下濱俊
  • Organizer: 第38回日本認知症学会学術集会
• [Presentation] Rat Bone Marrow-derived MSC Improve Oxidative Stress in Alzheimer’s Disease Mouse Model. (2018)
  • Author(s): Kazuki Yokokawa, Naotoshi Iwahara, Miho C. Emoto, Shin Hisahara, Naoki Gamou, Taro Saito, Mai Fujikura, Tatsuo Manabe, Takashi Matsushita, Akihiro Matsumura, Syuuichirou Suzuki, Jun Kawamata, Hirotada G. Fujii, Shun Shimohama
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] シンポジウム「認知症と再生医療」 間葉系幹細胞によるアルツハイマー病の治療 モデルマウスでの検討を通じて (2018)
  • Author(s): 横川和樹, 下濱俊
  • Organizer: 第37回日本認知症学会学術集会
• [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, 岩原直敏, 江本美穂, 久原真, 蒲生直希, 齋藤太郎, 藤倉舞, 眞部建郎, 鈴木紘美, 松下隆司, 松村晃寛, 鈴木秀一郎, 川又純, 藤井博匡, 下濱俊
  • Organizer: 第37回日本認知症学会学術集会
• [Presentation] Rat Bone Marrow-derived MSC Improve Oxidative Stress in Alzheimer’s Disease Mouse Model. (2018)
  • Author(s): Kazuki Yokokawa, Naotoshi Iwahara, Miho C. Emoto, Shin Hisahara, Naoki Gamou, Taro Saito, Mai Fujikura, Tatsuo Manabe, Takashi Matsushita, Akihiro Matsumura, Syuuichirou Suzuki, Jun Kawamata, Hirotada G. Fujii, and Shun Shimohama
  • Organizer: 第58回日本神経学会学術大会
• [Presentation] Transplantation of Rat Bone Marrow-derived Mesenchymal Stem Cells Regulates Oxidative Stress in Alzheimer’s Disease Transgenic Mouse Model. (2017)
  • Author(s): Kazuki Yokokawa, Naotoshi Iwahara, Miho C. Emoto, Shin Hisahara, Taro Saito, Mai Fujikura, Tatsuo Manabe, Hiromi Suzuki, Takashi Matsushita, Akihiro Matsumura, Syuuichirou Suzuki, Jun Kawamata, Hirotada G. Fujii, and Shun Shimohama
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] 骨髄間葉系幹細胞によるアルツハイマー病治療における脳内酸化ストレス動態の検討 (2017)
  • Author(s): 横川和樹, 岩原直敏, 江本美穂, 久原真, 齋藤太郎, 藤倉舞, 眞部建郎, 鈴木紘美, 松下隆司, 松村晃寛, 鈴木秀一郎, 川又純, 藤井博匡, 下濱俊
  • Organizer: 第36回日本認知症学会学術集会