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The anti-amyloid compound DO1 decreases plaque pathology and neuroinflammation-related expression changes in 5xFAD transgenic mice

Item Type:Article
Title:The anti-amyloid compound DO1 decreases plaque pathology and neuroinflammation-related expression changes in 5xFAD transgenic mice
Creators Name:Boeddrich, A. and Babila, J.T. and Wiglenda, T. and Diez, L. and Jacob, M. and Nietfeld, W. and Huska, M.R. and Haenig, C. and Groenke, N. and Buntru, A. and Blanc, E. and Meier, J.C. and Vannoni, E. and Erck, C. and Friedrich, B. and Martens, H. and Neuendorf, N. and Schnoegl, S. and Wolfer, D.P. and Loos, M. and Beule, D. and Andrade-Navarro, M.A. and Wanker, E.E.
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.
Keywords:Alzheimer's Disease, Small Molecules, Fluorescence Polarization Assay, Seed-Mediated, Protein Aggregation, Protein Misfolding, Neuroinflammation-Related Gene Expression, DO1, Aß1-42, Amyloid, 5xFAD Mouse Model, Animals, Mice
Source:Cell Chemical Biology
ISSN:2451-9448
Publisher:Cell Press (U.S.A.)
Volume:26
Number:1
Page Range:109-120
Date:17 January 2019
Official Publication:https://doi.org/10.1016/j.chembiol.2018.10.013
PubMed:View item in PubMed

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