期刊
CELL CHEMICAL BIOLOGY
卷 26, 期 1, 页码 109-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2018.10.013
关键词
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资金
- GO-Bio Initiative of the German Federal Ministry for Education and Research (BMBF) [0313881]
- ERA-NET NEURON initiative - BMBF [01W1301]
- Berlin Institute of Health Collaborative Research - BMBF [1.1.2.a.3]
- Helmholtz Validation Fund - Helmholtz Association, Germany [HVF-0013]
- Max Delbruck Center for Molecular Medicine in the Helmholtz Association
- BMBF (Era-Net NEURON II CIPRESS)
- Helmholtz Association [VH-NG-246]
- Deutsche Forschungsgemeinschaft DFG (Priority Program) [SPP 1784 ME2075/7-1]
- European Union FP7 EUROSPIN [HEALTH-F2-2009-241498]
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.
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