JNJ-38877618

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.

Background. It is known that, in vitro, human skin bacteria are able to split disperse azo dyes into the corresponding aromatic amines, some of which are sensitizers in the local lymph node assay. We hypothesize that the molecules of disperse dyes migrate onto the skin while garments are worn, and are metabolized and degraded by commensal skin bacteria. These molecules penetrate the skin and induce sensitization.Objectives. To evaluate the elicitation capacities of the possible azo‐degradation products of the selected azo disperse dyes in patients allergic to them and to compare it with the elicitation capacities of other para‐compunds.Methods. Ten patients allergic to Disperse Yellow 3 (DY3) and/or Disperse Orange 1 (DO1) were patch tested with a dilution series of the purified dyes 4‐nitroaniline and p‐aminodiphenylamine in concentrations equimolar to those of purified DO1 in the dilution series, as well as 4‐aminoacetanilide and 2‐amino‐p‐cresol in concentrations equimolar to those of purified DY3 in the dilution series.Results. Three patterns of patch test reactions could be seen. The 6 patients who were positive to DO1 and DY3 also reacted to p‐aminodiphenylamine and 2‐amino‐p‐cresol. Two patients were positive to DO1 only, and both reacted to p‐aminodiphenylamine, but to neither 4‐aminoacetanilide or 2‐amino‐p‐cresol. Two patients did not react to DO1 or DY3 on this occasion.Conclusion. We show that it is possible that the major sensitizers in contact allergy to DO1 and DY3 are their metabolites, p‐aminodiphenylamine and 2‐amino‐p‐cresol, respectively, which might be formed by the azoreductase pathway of skin bacteria.