1. The Anti-amyloid Compound DO1 Decreases Plaque Pathology and Neuroinflammation-Related Expression Changes in 5xFAD Transgenic Mice
- Author
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Nancy Neuendorf, Miguel A. Andrade-Navarro, Nicole Groenke, Erich E. Wanker, David P. Wolfer, Eric Blanc, Sigrid Schnoegl, Wilfried Nietfeld, Christian Erck, Elisabetta Vannoni, Dieter Beule, Christian Haenig, Beate Friedrich, Annett Boeddrich, Julius Tachu Babila, Henrik Martens, Manuela Jacob, Alexander Buntru, Jochen C. Meier, Thomas Wiglenda, Maarten Loos, Lisa Diez, Matthew R. Huska, University of Zurich, and Wanker, Erich E
- Subjects
Male ,Genetically modified mouse ,1303 Biochemistry ,Amyloid ,10017 Institute of Anatomy ,Clinical Biochemistry ,Mice, Transgenic ,Plaque, Amyloid ,610 Medicine & health ,Biology ,Protein aggregation ,1308 Clinical Biochemistry ,01 natural sciences ,Biochemistry ,Polymerization ,Pathogenesis ,Mice ,Protein Aggregates ,Structure-Activity Relationship ,Alzheimer Disease ,Gene expression ,Drug Discovery ,1312 Molecular Biology ,Animals ,Coloring Agents ,Molecular Biology ,Neuroinflammation ,Inflammation ,Pharmacology ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,3002 Drug Discovery ,Brain ,Small molecule ,Molecular medicine ,0104 chemical sciences ,Cell biology ,Mice, Inbred C57BL ,3004 Pharmacology ,10036 Medical Clinic ,1313 Molecular Medicine ,570 Life sciences ,biology ,Molecular Medicine ,Female ,Azo Compounds - Abstract
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.
- Published
- 2019