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

Mol Cell Biol. 2020 Feb 27;40(6):e00467-19. doi: 10.1128/MCB.00467-19. Print 2020 Feb 27.

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; MALDI-MSI; Nrf2; glutathione; inflammation; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics*
  • Animals
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology
  • Calcium-Binding Proteins / metabolism
  • Cognition / drug effects
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / metabolism
  • Disease Models, Animal
  • Glutathione / blood
  • Inflammation / pathology
  • Isothiocyanates / pharmacology
  • Kelch-Like ECH-Associated Protein 1 / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microfilament Proteins / metabolism
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress / physiology*
  • Phosphatidylethanolamines / metabolism
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / pathology
  • Plasmalogens / metabolism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

  • 6-(Methylsulfinyl)hexyl isothiocyanate
  • APP protein, mouse
  • Aif1 protein, mouse
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Calcium-Binding Proteins
  • Isothiocyanates
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • Microfilament Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Phosphatidylethanolamines
  • Plasmalogens
  • phosphatidylethanolamine
  • Glutathione