Changes in Glutathione Redox Potential Are Linked to Aβ42-Induced Neurotoxicity

Cell Rep. 2018 Aug 14;24(7):1696-1703. doi: 10.1016/j.celrep.2018.07.052.

Abstract

Glutathione is the major low-molecular weight thiol of eukaryotic cells. It is central to one of the two major NADPH-dependent reducing systems and is likely to play a role in combating oxidative stress, a process suggested to play a key role in Alzheimer's disease (AD). However, the nature and relevance of redox changes in the onset and progression of AD are still uncertain. Here, we combine genetically encoded redox sensors with our Drosophila models of amyloid-beta (Aβ) aggregation. We find that changes in glutathione redox potential (EGSH) closely correlate with disease onset and progression. We observe this redox imbalance specifically in neurons, but not in glia cells. EGSH changes and Aβ42 deposition are also accompanied by increased JNK stress signaling. Furthermore, pharmacologic and genetic manipulation of glutathione synthesis modulates Aβ42-mediated neurotoxicity, suggesting a causal relationship between disturbed glutathione redox homeostasis and early AD pathology.

Keywords: Alzheimer’s disease; Drosophila models; amyloid-beta; glutathione redox balance; redox sensors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Disease Progression
  • Drosophila melanogaster
  • Gene Expression Regulation / drug effects*
  • Genes, Reporter
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism
  • Glutaredoxins / genetics
  • Glutaredoxins / metabolism
  • Glutathione / metabolism*
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Homeostasis / genetics
  • Humans
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • MAP Kinase Signaling System
  • Neuroglia / cytology
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Oxidation-Reduction
  • Oxidative Stress
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Peptide Fragments / toxicity*
  • Protein Aggregates / genetics
  • Protein Aggregation, Pathological / genetics*
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / pathology

Substances

  • Amyloid beta-Peptides
  • Glutaredoxins
  • Luminescent Proteins
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • fluorescent protein 583
  • Green Fluorescent Proteins
  • Glutathione Peroxidase
  • Glutamate-Cysteine Ligase
  • Glutathione