Role of Nrf2 in Alzheimer's disease with diabetes mellitus

• Project/Area Number: 17K01837
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• 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): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: アルツハイマー病 / Nrf2 / 酸化ストレス / 神経炎症 / グルタチオン / 認知症 / 神経科学 / 糖尿病

Outline of Final Research Achievements

The increase in the number of elderly people and the increase in the number of patients with dementia has become a social problem in Japan. Nrf2 induces the expression of antioxidant enzyme genes in response to oxidative stress and suppresses the expression of inflammatory cytokine genes. Genetic Nrf2 induction model mice were crossed with Alzheimer's disease model to generate double mutant Nrf2 induced Alzheimer's disease model mice. Nrf2 induction in the brain of Alzheimer's disease model mice increased glutathione synthesis, and suppresses the induction of disease-associated microglia observed in the brains of Alzheimer's disease model mice, resulting in suppression of neuropathy around amyloid plaques.

Academic Significance and Societal Importance of the Research Achievements

我が国では、高齢者数の増加から認知症の患者数増加が社会問題になっている。転写因子Nrf2は、酸化ストレスや炎症を抑制することが知られる。Nrf2を活性化する作用のある薬剤が臨床治験中であることから、Nrf2は、各種疾患の治療標的分子として期待されている。本研究において、Nrf2活性化アルツハイマー病モデルマウスを作出して解析を行ったところ、脳内で酸化ストレスを低下させる分子であるグルタチオンが増加し、さらに、アルツハイマー病で認められる神経炎症が低下し、認知機能異常が改善した。以上から、Nrf2活性化がアルツハイマー病の治療に有効である可能性が示された。

Research Products

• [Journal Article] Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-in Alzheimer’s Disease Model Mice. (2020)
  • Author(s): 3)(*Equal contribution) Uruno A*, Matsumaru D*, Ryoke R, Saito R, Kadoguchi S, Saigusa D, Saito T, Saido TC, Kawashima R, Yamamoto M.
  • Journal Title: Mol Cell Biol. Volume: 40 Issue: 6
  • DOI: 10.1128/mcb.00467-19
  • 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] Multiple measurements of the urinary sodium-to-potassium ratio strongly related home hypertension: TMM Cohort Study. (2020)
  • Author(s): Kogure M, Hirata T, Nakaya N, Tsuchiya N, Nakamura T, Narita A, Miyagawa K, Koshimizu H, Obara T, Metoki H, Uruno A, Kikuya M, Sugawara J, Kuriyama S, Tsuji I, Kure S, Hozawa A.
  • Journal Title: Hypertens Res Volume: 43 Issue: 1 Pages: 62-71
  • DOI: 10.1038/s41440-019-0335-2
  • Peer Reviewed
• [Journal Article] Reduced Sleep Efficiency, Measured Using an Objective Device, Was Related to an Increased Prevalence of Home Hypertension in Japanese Adults (2020)
  • Author(s): Hirata T, Nakamura T, Kogure M, Tsuchiya N, Narita A, Miyagawa K, Nochioka K, Uruno A, Obara T, Nakaya N, Metoki H, Kikuya M, Sugawara J, Kuriyama S, Tsuji I, Kure S, Hozawa A.
  • Journal Title: Hypertens Res Volume: 43 Issue: 1 Pages: 23-29
  • DOI: 10.1038/s41440-019-0329-0
  • Peer Reviewed
• [Journal Article] Alteration of the lysophosphatidic acid and its precursor lysophosphatidylcholine levels in spinal cord stenosis: A study using a rat cauda equina compression model. (2019)
  • Author(s): Uranbileg B, Ito N, Kurano M, Saigusa D, Saito R, Uruno A, Kano K, Ikeda H, Yamada Y, Sumitani M, Sekiguchi M, Aoki J, Yatomi Y.
  • Journal Title: Scientific reports Volume: 9 Issue: 1 Pages: 16578-16578
  • DOI: 10.1038/s41598-019-52999-5
  • Peer Reviewed / Open Access
• [Journal Article] Conductive Adhesive Film Expands the Utility of Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (2019)
  • Author(s): Saigusa D, Saito R, Kawamoto K, Uruno A, Kano K, Aoki J, Yamamoto M, Kawamoto T.
  • Journal Title: Anal Chem Volume: 91 Issue: 14 Pages: 8979-8986
  • DOI: 10.1021/acs.analchem.9b01159
  • Peer Reviewed / Open Access
• [Journal Article] Identification of celastramycin as a novel therapeutic agent for pulmonary arterial hypertension: high-throughput screening of 5,562 compounds (2019)
  • Author(s): Kurosawa R, Satoh K, Kikuchi N, Kikuchi H, Saigusa D, Elias-Al-Mamun M, Siddique MAH, Omura J, Satoh T, Sunamura S, Nogi M, Numano K, Miyata S, Uruno A, Kano K, Matsumoto Y, Doi T, Aoki J, Oshima Y, Yamamoto M, Shimokawa H
  • Journal Title: Circ Res Volume: 125 Issue: 3 Pages: 309-327
  • DOI: 10.1161/circresaha.119.315229
  • Peer Reviewed / Open Access
• [Journal Article] Nrf2 activation in myeloid cells and endothelial cells differentially mitigates sickle cell disease pathology in mice. (2019)
  • Author(s): Keleku-Lukwete N, Suzuki M, Panda H, Otsuki A, Katsuoka F, Saito R, Saigusa D, Uruno A, Yamamoto M.
  • Journal Title: Blood Adv Volume: 3 Issue: 8 Pages: 1285-1297
  • DOI: 10.1182/bloodadvances.2018017574
  • Peer Reviewed
• [Journal Article] Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals (2019)
  • Author(s): Yamaguchi-Kabata, Y.,（途中略）,Koshiba, S., （途中略）, Tohoku Medical Megabank Project Study Group.（合計１9名、本研究者は５番目）
  • Journal Title: Hum. Genet. Volume: 印刷中 Issue: 4 Pages: 389-409
  • DOI: 10.1007/s00439-019-01998-7
  • Peer Reviewed / Open Access
• [Journal Article] Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice. (2019)
  • Author(s): Yagishita Y, Uruno A, Chartoumpekis DV, Kensler TW, Yamamoto M.
  • Journal Title: J Endocrinol Volume: 未定 Issue: 3 Pages: 403-416
  • DOI: 10.1530/joe-18-0355
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intracellular S1P Levels Dictate Fate of Different Regions of the Hippocampus following Transient Global Cerebral Ischemia. (2018)
  • Author(s): Rashad S, Niizuma K, Saigusa D, Han X, Sato-Maeda M, Saito R, Uruno A, Fujimura M, Ikawa S, Yamamoto M, Tominaga T.
  • Journal Title: Neuroscience Volume: 384 Pages: 188-202
  • DOI: 10.1016/j.neuroscience.2018.05.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metabolomic Analysis of Mouse Brain after a Transient Middle Cerebral Artery Occlusion by Mass Spectrometry Imaging (2018)
  • Author(s): Abe T, Niizuma K, Kanoke A, Saigusa D, Saito R, Uruno A, Fujimura M, Yamamoto M, Tominaga T.
  • Journal Title: Neurologia medico-chirurgica Volume: 58 Issue: 9 Pages: 384-392
  • DOI: 10.2176/nmc.oa.2018-0054
  • NAID: 130007484209
  • ISSN: 0470-8105, 1349-8029
  • Peer Reviewed / Open Access
• [Journal Article] Metabolomic changes in the mouse retina after optic nerve injury. (2018)
  • Author(s): Sato K, Saigusa D, Saito R, Fujioka A, Nakagawa Y, Nishiguchi KM, Kokubun T, Motoike IN, Maruyama K, Omodaka K, Shiga Y, Uruno A, Koshiba S, Yamamoto M, Nakazawa T.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 11930-11930
  • DOI: 10.1038/s41598-018-30464-z
  • Peer Reviewed / Open Access
• [Journal Article] The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. (2017)
  • Author(s): Higashi C, Kawaji A, Tsuda N, Hayashi M, Saito R, Yagishita Y, Suzuki T, Uruno A, Nakamura M, Nakao K, Furusako S, Yamamoto M.
  • Journal Title: Eur J Pharmacol Volume: 802 Pages: 76-84
  • DOI: 10.1016/j.ejphar.2017.02.044
  • Peer Reviewed / Open Access
• [Journal Article] High glucose stimulates expression of aldosterone synthase (CYP11B2) and secretion of aldosterone in human adrenal cells (2017)
  • Author(s): Shimada Hiroki、Kogure Naotaka、Noro Erika、Kudo Masataka、Sugawara Kaori、Sato Ikuko、Shimizu Kyoko、Kobayashi Makoto、Suzuki Dai、Parvin Rehana、Saito-Ito Takako、Uruno Akira、Saito-Hakoda Akiko、Rainey William E.、Ito Sadayoshi、Yokoyama Atsushi、Sugawara Akira
  • Journal Title: FEBS Open Bio Volume: 7 Issue: 9 Pages: 1410-1421
  • DOI: 10.1002/2211-5463.12277
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The multiple functions of Nrf2 in diabetes mellitus and obesity (2019)
  • Author(s): Uruno A
  • Organizer: The Environmental Response V
  • Int'l Joint Research / Invited
• [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/
• [Remarks] Nrf2活性化によるアルツハイマー病改善作用の解明
  • URL: https://www.tohoku.ac.jp/japanese/2020/01/press20200121-02-nrf2.html
• [Patent(Industrial Property Rights)] 生体組織上の還元型グルタチオン分布を測定する方法及び診断用データの取得方法 (2019)
  • Inventor(s): 山本雅之、宇留野晃、三枝大輔、齋藤律水
  • Industrial Property Rights Holder: 山本雅之、宇留野晃、三枝大輔、齋藤律水
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-122085
  • Filing Date: 2019