| First Author | Boeddrich A | Year | 2019 |
| Journal | Cell Chem Biol | Volume | 26 |
| Issue | 1 | Pages | 109-120.e7 |
| PubMed ID | 30472115 | Mgi Jnum | J:284805 |
| Mgi Id | MGI:6389877 | Doi | 10.1016/j.chembiol.2018.10.013 |
| Citation | Boeddrich A, et al. (2019) The Anti-amyloid Compound DO1 Decreases Plaque Pathology and Neuroinflammation-Related Expression Changes in 5xFAD Transgenic Mice. Cell Chem Biol 26(1):109-120.e7 |
| abstractText | Self-propagating amyloid-beta (Abeta) 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 Abeta42 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 Abeta42 polymerization at substoichiometric concentrations. Mechanistic studies revealed that DO1 disrupts preformed fibrillar assemblies of synthetic Abeta42 peptides and decreases the seeding activity of Abeta aggregates from brain extracts of AD transgenic mice. DO1 also reduced the size and abundance of diffuse Abeta 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 Abeta structures with small molecules as a valid therapeutic strategy. |
