Glutathione regulations in Alzheimer's disease

• Project/Area Number: 20K07352
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Uruno Akira 東北大学, 東北メディカル・メガバンク機構, 准教授 (90396474)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: アルツハイマー病 / グルタチオン / アミノ酸 / Keap1-Nrf2系 / Nrf2

Outline of Research at the Start

我が国では、認知症の患者数増加が大きな問題になっているが、酸化ストレスや炎症が認知症に関係することが報告されてきた。Nrf2は、ストレス応答性遺伝子発現調節因子であるが、酸化ストレスを消去するための分子グルタチオンの調節に大きく貢献している。このため、モデルマウスを利用した解析により、認知症で引き起こる脳内のグルタチオン代謝異常やNrf2活性化による脳グルタチオン代謝改善作用の改善を目指す。

Outline of Final Research Achievements

Metabolome analysis showed differences in metabolite levels in brain tissue between the wild-type and Alzheimer's disease model mice. Genetic and pharmacological Nrf2 inductions suppressed the metabolic changes. Amino acids including N-acetylaspartate, aspartate, glutamate contributed to the metabolic changes in Alzheimer's disease model mouse brains. qRT-PCR analyses revealed that the expression levels of metabolism-related enzyme genes were altered in the brains of Alzheimer's disease model mice. These results demonstrate that metabolism of amino acids is altered in Alzheimer's disease brains and the Keap1-Nrf2 system contributes to maintenance of the metabolic regulations.

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー病モデルマウスの脳では、アミノ酸代謝変化が生じていた。遺伝子改変および薬剤によるNrf2活性化は、このアルツハイマー病で引き起こるアミノ酸代謝異常を抑制していた。Nrf2はアルツハイマー病の新たな治療標的として期待されているが、従来の報告による酸化ストレスおよび神経炎症の抑制作用に加えて、本研究成果より代謝恒常性維持作用を発揮してアルツハイマー病の病態を抑制することが示された。

Research Products

• [Journal Article] Combined Fat Mass and Fat-free Mass Indices and Lung Function Among Japanese Population: The Tohoku Medical Megabank Community-based Cohort Study (2024)
  • Author(s): Takase Masato、Uruno Akira et al.
  • Journal Title: Journal of Epidemiology Volume: 34 Issue: 3 Pages: 119-128
  • DOI: 10.2188/jea.JE20220355
  • ISSN: 0917-5040, 1349-9092
  • Year and Date: 2024-03-05
  • Peer Reviewed
• [Journal Article] The Association of Lung Function and Carotid Intima-Media Thickness in a Japanese Population: The Tohoku Medical Megabank Community-Based Cohort Study (2023)
  • Author(s): Masato Takase, Mitsuhiro Yamada, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 30 Issue: 8 Pages: 1022-1044
  • DOI: 10.5551/jat.63826
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2023-08-01
  • Peer Reviewed / Open Access
• [Journal Article] Associations between the Combined Fat Mass Index and Fat-Free Mass Index with Carotid Intima-Media Thickness in a Japanese Population: The Tohoku Medical Megabank Community-Based Cohort Study (2023)
  • Author(s): Takase Masato、Nakamura Tomohiro、Nakaya Naoki、Kogure Mana、Hatanaka Rieko、Nakaya Kumi、Kanno Ikumi、Nochioka Kotaro、Tsuchiya Naho、Hirata Takumi、Hamanaka Yohei、Sugawara Junichi、Suzuki Kichiya、Fuse Nobuo、Uruno Akira、N Kodama Eiichi、Kuriyama Shinichi、Tsuji Ichiro、Kure Shigeo、Hozawa Atsushi
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 30 Issue: 3 Pages: 255-273
  • DOI: 10.5551/jat.63523
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2023-03-01
  • Peer Reviewed
• [Journal Article] The KEAP1-NRF2 system and neurodegenerative diseases (2023)
  • Author(s): Uruno Akira、Yamamoto Masayuki
  • Journal Title: Antioxidants & Redox Signaling
  • DOI: 10.1089/ars.2023.0005
  • Peer Reviewed / Open Access
• [Journal Article] Association between lung function and hypertension and home hypertension in a Japanese population: the Tohoku Medical Megabank Community-Based Cohort Study (2023)
  • Author(s): Masato Takase, Mitsuhiro Yamada, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, et al.
  • Journal Title: Journal of hypertension Volume: 41 Pages: 443-452
  • DOI: 10.1097/hjh.0000000000003356
  • Peer Reviewed / Open Access
• [Journal Article] Design and Progress of Child Health Assessments at Community Support Centers in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank Project (2023)
  • Author(s): Kobayashi T, Kobayashi M, Minegishi N, Kikuya M, Obara T, Ishikuro M, Yamanaka C, Onuma T, Murakami K, Ueno F, Noda A, Uruno A, Sugawara J, Suzuki K, Kodama EN, Hamanaka Y, Tsuchiya M, Kogure M, Nakaya N, Taira M, Sakurai-Yageta M, Tamahara T, Kawashima J, Goto M, Otsuki A, Shimizu R,Ogishima A,1, Hashizume H, et al.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 259 Issue: 2 Pages: 93-105
  • DOI: 10.1620/tjem.2022.J103
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] A Pilot Study for Return of Individual Pharmacogenomic Results to Population-Based Cohort Study Participants (2022)
  • Author(s): Ohneda K, Hiratsuka M, Kawame H et al.
  • Journal Title: JMA Journal Volume: 5 Issue: 2 Pages: 177-189
  • DOI: 10.31662/jmaj.2021-0156
  • ISSN: 2433-328X, 2433-3298
  • Year and Date: 2022-04-15
  • Peer Reviewed / Open Access
• [Journal Article] Maternal Baseline Characteristics and Perinatal Outcomes: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (2022)
  • Author(s): Sugawara, J.,et al., Koshiba, S., et al., Yamamoto, M.（合計32名、本研究者は21番目）
  • Journal Title: Journal of Epidemiology Volume: 32 Issue: 2 Pages: 69-79
  • DOI: 10.2188/jea.JE20200338
  • NAID: 130008157950
  • ISSN: 0917-5040, 1349-9092
  • Year and Date: 2022-02-05
  • Peer Reviewed / Open Access
• [Journal Article] Nrf2 deficiency deteriorates diabetic kidney disease in Akita model mice (2022)
  • Author(s): Liu Yexin、Uruno Akira、Saito Ritsumi、Matsukawa Naomi、Hishinuma Eiji、Saigusa Daisuke、Liu Hong、Yamamoto Masayuki
  • Journal Title: Redox Biology Volume: 58 Pages: 102525-102525
  • DOI: 10.1016/j.redox.2022.102525
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan (2022)
  • Author(s): Fuse N, Sakurai M, Motoike IN., Kojima K, Takai-Igarashi T, et al.
  • Journal Title: Ophthalmology Science Volume: 2 Issue: 1 Pages: 100113-100113
  • DOI: 10.1016/j.xops.2022.100113
  • Peer Reviewed / Open Access
• [Journal Article] Halofuginone micelle nanoparticles eradicate Nrf2-activated lung adenocarcinoma without systemic toxicity (2022)
  • Author(s): Panda Harit、Suzuki Mikiko、Naito Mitsuru、Saito Ritsumi、Wen Huaichun、Baird Liam、Uruno Akira、Miyata Kanjiro、Yamamoto Masayuki
  • Journal Title: Free Radical Biology and Medicine Volume: 187 Pages: 92-104
  • DOI: 10.1016/j.freeradbiomed.2022.05.017
  • Peer Reviewed / Open Access
• [Journal Article] Consideration of the reference value and number of measurements of the urinary sodium-to-potassium ratio based on the prevalence of untreated home hypertension: TMM Cohort Study (2022)
  • Author(s): Kogure Mana、Uruno Akira et al.
  • Journal Title: Hypertension Research Volume: 45 Issue: 5 Pages: 866-875
  • DOI: 10.1038/s41440-021-00843-7
  • Peer Reviewed
• [Journal Article] Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel (2022)
  • Author(s): Suzuki Norio、Iwamura Yuma、Nakai Taku、Kato Koichiro、Otsuki Akihito、Uruno Akira、Saigusa Daisuke、Taguchi Keiko、Suzuki Mikiko、Shimizu Ritsuko、Yumoto Akane、Okada Risa、Shirakawa Masaki、Shiba Dai、Takahashi Satoru、Suzuki Takafumi、Yamamoto Masayuki
  • Journal Title: Kidney International Volume: 101 Issue: 1 Pages: 92-105
  • DOI: 10.1016/j.kint.2021.09.031
  • Peer Reviewed / Open Access
• [Journal Article] Nrf2 plays a critical role in the metabolic response during and after spaceflight (2021)
  • Author(s): Uruno A、Saigusa D、Suzuki T、Yumoto A、Nakamura T、Matsukawa N、Yamazaki T、Saito R、Taguchi K、Suzuki M、Suzuki N、Otsuki A、Katsuoka F、Hishinuma E、Okada R、Koshiba S、Tomioka Y、Shimizu R、Shirakawa M、Kensler TW.、Shiba D、Yamamoto M
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 1381-1381
  • DOI: 10.1038/s42003-021-02904-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel method for evaluating the health condition of mice in space through a video downlink (2021)
  • Author(s): YUMOTO Akane、KOKUBO Toshiaki、IZUMI Ryutaro、SHIMOMURA Michihiko、FUNATSU Osamu、TADA Motoki N.、OTA-MURAKAMI Naoko、IINO Kayoko、SHIRAKAWA Masaki、MIZUNO Hiroyasu、KUDO Takashi、TAKAHASHI Satoru、SUZUKI Takafumi、URUNO Akira、YAMAMOTO Masayuki、SHIBA Dai
  • Journal Title: Experimental Animals Volume: 70 Issue: 2 Pages: 236-244
  • DOI: 10.1538/expanim.20-0102
  • NAID: 130008037417
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed
• [Journal Article] Impacts of the urinary sodium-to-potassium ratio, sleep efficiency, and conventional risk factors on home hypertension in a general Japanese population (2021)
  • Author(s): Hirata T, Kogure M, Tsuchiya N, Miyagawa K, Narita A, Nochioka K, Uruno A, Obara T, Nakamura T, Nakaya N, Metoki H, Kikuya M, Sugawara J, Kuriyama S, Tsuji I, Kure S, Hozawa A.
  • Journal Title: Hypertens Res Volume: - Issue: 7 Pages: 858-865
  • DOI: 10.1038/s41440-021-00628-y
  • Peer Reviewed
• [Journal Article] Metabolic Basis of Neuronal Vulnerability to Ischemia; An in Vivo Untargeted Metabolomics Approach (2020)
  • Author(s): Rashad S, Saigusa D, Yamazaki T, Matsumoto Y, Tomioka Y, Saito R, Uruno A, Niizuma K, Yamamoto M, Tominaga T.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 6507-6507
  • DOI: 10.1038/s41598-020-63483-w
  • Peer Reviewed / Open Access
• [Journal Article] Nrf2 contributes to the weight gain of mice during space travel (2020)
  • Author(s): Suzuki, T., et al., Koshiba, S. et al., Yamamoto, M.（合計37名、本研究者は18番目）
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 496-496
  • DOI: 10.1038/s42003-020-01227-2
  • NAID: 120007161347
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] アルツハイマー病における脳内グルタチオンおよびアミノ酸代謝の検討 (2021)
  • Author(s): 古川奈々花, 宇留野晃, 齋藤律水, 三枝大輔, 斉藤貴志, 西道隆臣, 本橋ほづみ, 山本雅之
  • Organizer: 日本生化学会 東北支部 第87回例会・シンポジウム
• [Book] 生物の寿命延長 (2022)
  • Author(s): 南野 徹
  • Total Pages: 460
  • Publisher: エヌ・ティー・エス
  • ISBN: 486043773X
• [Remarks] 東北大学大学院医学系研究科医化学分野
  • URL: http://www.dmbc.med.tohoku.ac.jp/official/
• [Remarks] 転写因子Nrf2による糖尿病性腎臓障害の保護作用
  • URL: https://www.megabank.tohoku.ac.jp/news/51617
• [Remarks] ストレス対応で宇宙環境に身体をアジャスト！ ストレス応答性転写因子Nrf2の宇宙における脂質代謝調節
  • URL: https://www.megabank.tohoku.ac.jp/news/47160
• [Remarks] 東北大学大学院医学系研究科医化学分野
  • URL: http://www.dmbc.med.tohoku.ac.jp/official/index.html