Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-In Alzheimer's Disease Model Mice

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 (App(NLGF)) mice were studied in combination with genetic Nrf2 induction model Keap1(FA/FA) mice. While App(NLGF) mice displayed shorter latency to escape than wild-type mice in the passive-avoidance task, the impairment was improved in App(NLGF)::Keap1(FA/FA) mice. Matrix-assisted laser desorption ionization-mass spectrometry imaging revealed that reduced glutathione levels were elevated by Nrf2 induction in App(NLGF)::Keap1(FA/FA) mouse brains compared to App(NLGF) mouse brains. Genetic Nrf2 induction in App(NLGF) mice markedly suppressed the elevation of the oxidative stress marker 8-OHdG and lba1-positive microglial cell number. We also determined the plasmalogen-phosphatidylethanolamine (PIsPE) level as an AD biomarker. PIsPE containing polyunsaturated fatty acids was decreased in the App(NLGF) 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(methylsulfinyflhexyl isothiocyanate]. Administration of 6-MSITC improved the impaired cognition of App(NLGF) 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.