1. Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-in Alzheimer's Disease Model Mice.
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Akira Uruno, Daisuke Matsumaru, Rie Ryoke, Ritsumi Saito, Shiori Kadoguchi, Daisuke Saigusa, Takashi Saito, Saido, Takaomi C., Ryuta Kawashima, and Masayuki Yamamoto
- Subjects
ALZHEIMER'S disease ,OXIDATIVE stress ,MOUSE diseases ,MEDICAL model ,UNSATURATED fatty acids - 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 App
NL-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 (MALDI-MSI) revealed that reduced glutathione levels were elevated by Nrf2 induction in AppNLGF ::Keap1FA/FA mouse brains compared with 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. Administration of 6-MSITC improved the impaired cognition of App 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. [ABSTRACT FROM AUTHOR]NLGF - Published
- 2020
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