Mechanisms of redox perturbation in the mouse model of Alzheimer's disease

• Project/Area Number: 15K19036
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Hashimoto Shoko 国立研究開発法人理化学研究所, 脳科学総合研究センター, 基礎科学特別研究員 (50632890)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: アルツハイマー病 / 酸化ストレス / グルタチオン / 神経炎症 / グルタチオン量低下マウス

Outline of Final Research Achievements

Oxidative stress is demonstrated to play an important role in the etiology of Alzheimer’s disease (AD). In order to defense against oxidative stress, organisms possess glutathione as an important antioxidant. However, glutathione level is decreased with ageing and progression of diseases including AD. We found that glutathione level is also lowered in App-knockin (App-KI) mice. In this study, we elucidated the mechanism by which glutathione level was decreased in App-KI, and the effect of glutathione reduction on AD progression. Consequently, we concluded that neuroinflammation induced by amyloid pathology decreased glutathione level, and resulted in further activation of neuroinflammation and neuronal cell death. The vicious cycle of neuroinflammation and oxidative stress may play an important role in AD progression.

Research Products

• [Journal Article] Critical Review: Involvement of Endoplasmic reticulum stress in the etiology of Alzheimer’s disease (2018)
  • Author(s): Shoko Hashimoto and Takaomi C. Saido
  • Journal Title: Open Biology Volume: 8: 180024 Issue: 4 Pages: 180024-180024
  • DOI: 10.1098/rsob.180024
  • Peer Reviewed / Open Access
• [Journal Article] Endoplasmic reticulum stress responses in mouse models of Alzheimer disease: overexpression paradigm versus knock-in paradigm (2018)
  • Author(s): Shoko Hashimoto, Ayano Ishii, Naoko Kamano, Naoto Watamura, Takashi Saito, Toshio Ohshima, Makoto Yokosuka, and Takaomi C. Saido
  • Journal Title: Journal of Biological Chemistry Volume: 293(9) Issue: 9 Pages: 3118-3125
  • DOI: 10.1074/jbc.m117.811315
  • Peer Reviewed
• [Presentation] The role of a novel Tau binding protein in the progression of Alzheimer's disease (2017)
  • Author(s): Shoko Hashimoto, Naoko Kamano, Yukio Matsuba, Per Nilsson, Shin-ichi Muramatsu, Takashi Saito, and Takaomi C. Saido
  • Organizer: EMBL Symposia: Mechanism of Neurodegeneration
  • Int'l Joint Research
• [Presentation] 新規アルツハイマー病関連因子による神経変性メカニズムの解明 (2017)
  • Author(s): 橋本翔子、釜野直子、松葉由紀夫、村松慎一、斉藤貴志、西道隆臣
  • Organizer: 第36回日本認知症学会学術集会
• [Presentation] グルタチオン量減少がアルツハイマー病病理に及ぼす影響の解析 (2017)
  • Author(s): 橋本翔子、釜野直子、石井綾乃、斉藤貴志、西道隆臣
  • Organizer: 2017年度生命科学系学会合同年次大会(Conbio2017)
• [Presentation] グルタチオン量減少がアルツハイマー病病理に及ぼす影響の解析 (2016)
  • Author(s): 橋本翔子、斉藤貴志、西道隆臣
  • Organizer: 第35回 日本認知症学会 学術集会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-12-01
• [Presentation] Mechanism of glutathione reduction in the 2nd generation mouse model of Alzheimer's disease (2016)
  • Author(s): Shoko Hashimoto, Takashi Saito, and Takaomi C. Saido
  • Organizer: SOCIETY for NEUROSCIENCE 2016
  • Place of Presentation: サンディエゴ（アメリカ）
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] 次世代型アルツハイマー病モデルマウス脳におけるグルタチオン量減少メカニズムの解析 (2015)
  • Author(s): 橋本翔子、斉藤貴志、西道隆臣
  • Organizer: 第88回日本生化学会大会
  • Place of Presentation: 神戸ポートピアホテル・神戸国際会議場・神戸国際展示場・神戸商工会議所 （兵庫県・神戸市）
  • Year and Date: 2015-12-01
• [Presentation] APPノックインマウスにおけるグルタチオン量減少メカニズムの解析 (2015)
  • Author(s): 橋本翔子、斉藤貴志、西道隆臣
  • Organizer: 第34回日本認知症学会学術集会
  • Place of Presentation: リンクステーションホール青森・ホテル青森 （青森県・青森市）
  • Year and Date: 2015-10-02
• [Book] Aging Mechanisms (2015)
  • Author(s): Shoko Hashimoto, Per Nilsson, and Takaomi C. Saido
  • Total Pages: 437
  • Publisher: Aging Mechanisms: Longevity, Metabolism, and Brain Aging” (Chapter 19 Catabolism and Anabolism of Abeta)