The Anti-amyloid Compound DO1 Decreases Plaque Pathology and Neuroinflammation-Related Expression Changes in 5xFAD Transgenic Mice

Cell Chem Biol. 2019 Jan 17;26(1):109-120.e7. doi: 10.1016/j.chembiol.2018.10.013. Epub 2018 Nov 21.


Self-propagating amyloid-β (Aβ) aggregates or seeds possibly drive pathogenesis of Alzheimer's disease (AD). Small molecules targeting such structures might act therapeutically in vivo. Here, a fluorescence polarization assay was established that enables the detection of compound effects on both seeded and spontaneous Aβ42 aggregation. In a focused screen of anti-amyloid compounds, we identified Disperse Orange 1 (DO1) ([4-((4-nitrophenyl)diazenyl)-N-phenylaniline]), a small molecule that potently delays both seeded and non-seeded Aβ42 polymerization at substoichiometric concentrations. Mechanistic studies revealed that DO1 disrupts preformed fibrillar assemblies of synthetic Aβ42 peptides and decreases the seeding activity of Aβ aggregates from brain extracts of AD transgenic mice. DO1 also reduced the size and abundance of diffuse Aβ plaques and decreased neuroinflammation-related gene expression changes in brains of 5xFAD transgenic mice. Finally, improved nesting behavior was observed upon treatment with the compound. Together, our evidence supports targeting of self-propagating Aβ structures with small molecules as a valid therapeutic strategy.

Keywords: 5xFAD mouse model; Alzheimer's disease; Aβ1-42; DO1; amyloid; fluorescence polarization assay; neuroinflammation-related gene expression; protein aggregation; protein misfolding; seed-mediated; small molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Azo Compounds / chemistry
  • Azo Compounds / pharmacology*
  • Brain / drug effects
  • Brain / metabolism
  • Coloring Agents / chemistry
  • Coloring Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Female
  • Inflammation / drug therapy*
  • Inflammation / genetics
  • Inflammation / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Structure
  • Plaque, Amyloid / drug therapy*
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / metabolism
  • Polymerization / drug effects
  • Protein Aggregates / drug effects
  • Structure-Activity Relationship


  • Amyloid beta-Peptides
  • Azo Compounds
  • Coloring Agents
  • Protein Aggregates
  • Disperse Orange 1