@article{982cfa08101b4057bf60cdea0bb0e41e,
title = "Nrf2 suppresses oxidative stress and inflammation in APP knock-in Alzheimer's disease model mice",
abstract = "Nrf2 (NF-E2-related-factor 2) is a stress-responsive transcription factor that protects cells against oxidative stresses. To clarify whether Nrf2 prevents Alzheimer's disease (AD), AD model AppNL-G-F/NL-G-F knock-in (AppNLGF) mice were studied in combination with genetic Nrf2 induction model Keap1FA/FA mice. While AppNLGF mice displayed shorter latency to escape than wild-type mice in the passive-avoidance task, the impairment was improved in AppNLGF::Keap1FA/FA mice. Matrix-assisted laser desorption ionization–mass spectrometry imaging revealed that reduced glutathione levels were elevated by Nrf2 induction in AppNLGF::Keap1FA/FA mouse brains compared to AppNLGF mouse brains. Genetic Nrf2 induction in AppNLGF mice markedly suppressed the elevation of the oxidative stress marker 8-OHdG and Iba1-positive microglial cell number. We also determined the plasmalogen-phosphatidylethanolamine (PlsPE) level as an AD biomarker. PlsPE containing polyunsaturated fatty acids was decreased in the AppNLGF mouse brain, but Nrf2 induction attenuated this decline. To evaluate whether pharmacological induction of Nrf2 elicits beneficial effects for AD treatment, we tested the natural compound 6-MSITC [6-(methylsulfinyl)hexyl isothiocyanate]. Administration of 6-MSITC improved the impaired cognition of AppNLGF mice in the passive-avoidance task. These results demonstrate that the induction of Nrf2 ameliorates cognitive impairment in the AD model mouse by suppressing oxidative stress and neuroinflammation, suggesting that Nrf2 is an important therapeutic target of AD.",
keywords = "Alzheimer's disease, Alzheimer's disease, Glutathione, Inflammation, MALDI-MSI, Nrf2, Nrf2, Oxidative stress",
author = "Akira Uruno and Daisuke Matsumaru and Rie Ryoke and Ritsumi Saito and Shiori Kadoguchi and Daisuke Saigusa and Takashi Saito and Saido, {Takaomi C.} and Ryuta Kawashima and Masayuki Yamamoto",
note = "Funding Information: This research was supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from the Japan Agency for Medical Research and Development (AMED; grant JP19am0101001 [M.Y.]), by the Tohoku Medical Megabank Project Funding Information: We thank Nao Ota (Tohoku University) and the Tohoku University Graduate School of Medicine Biomedical Research Core for technical support. This research was supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from the Japan Agency for Medical Research and Development (AMED; grant JP19am0101001 [M.Y.]), by the Tohoku Medical Megabank Project from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), by AMED (JP18km0105001 and JP18km0105002 [M.Y.]), by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS; grants 24249015 and 19H01019 [M.Y.], grants 17K01837 and 16KK0195 [A.U.], and grant 19K07361 [D.M.]), by the Takeda Science Foundation (M.Y.), and by the Naito Foundation (M.Y.). Funding Information: from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), by AMED (JP18km0105001 and JP18km0105002 [M.Y.]), by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS; grants 24249015 and 19H01019 [M.Y.], grants 17K01837 and 16KK0195 [A.U.], and grant 19K07361 [D.M.]), by the Takeda Science Foundation (M.Y.), and by the Naito Foundation (M.Y.). Publisher Copyright: Copyright {\textcopyright} 2020 American Society for Microbiology. All Rights Reserved.",
year = "2020",
month = mar,
day = "1",
doi = "10.1128/MCB.00467-19",
language = "English",
volume = "40",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "6",
}