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

Self-propagating amyloid-beta (A beta) 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 A beta 42 aggregation. In a focused screen of anti-amyloid compounds, we identified Disperse Orange 1 (DO1) ([4-((4-nitro-phenyl)diazenyl)-N-phenylaniline]), a small molecule that potently delays both seeded and non-seeded Ab42 polymerization at substoichiometric concentrations. Mechanistic studies revealed that DO1 disrupts preformed fibrillar assemblies of synthetic Ab42 peptides and decreases the seeding activity of Ab aggregates from brain extracts of AD transgenic mice. DO1 also reduced the size and abundance of diffuse Ab 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 A beta structures with small molecules as a valid therapeutic strategy.