The Anti-amyloid Compound DO1 Decreases Plaque Pathology and Neuroinflammation-Related Expression Changes in 5xFAD Transgenic Mice.

Autor:	Boeddrich A; Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Babila JT; Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Wiglenda T; Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Diez L; Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Jacob M; Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Nietfeld W; Genome Regulation, Max Planck Institut for Molecular Genetics, 14195 Berlin, Germany., Huska MR; Evolutionary and Cancer Genomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Haenig C; Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Groenke N; Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Buntru A; Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Blanc E; Core Unit Bioinformatics - CUBI, Berlin Institute of Health, 10117 Berlin, Germany., Meier JC; Division Cell Physiology, Technical University Braunschweig, 38106 Braunschweig, Germany., Vannoni E; Children's Hospital Zurich - Eleonore Foundation, University of Zurich, 8032 Zurich, Switzerland., Erck C; Synaptic Systems GmbH, 37079 Göttingen, Germany., Friedrich B; Synaptic Systems GmbH, 37079 Göttingen, Germany., Martens H; Synaptic Systems GmbH, 37079 Göttingen, Germany., Neuendorf N; Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Schnoegl S; Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany., Wolfer DP; Institute of Anatomy, University of Zurich and Institute of Human Movement Sciences and Sport, ETH Zurich, 8092 Zurich, Switzerland., Loos M; Sylics (Synaptologics B.V.), 1008 Amsterdam, Netherlands., Beule D; Core Unit Bioinformatics - CUBI, Berlin Institute of Health, 10117 Berlin, Germany., Andrade-Navarro MA; Institute of Molecular Biology, Computational Biology and Data Mining, Johannes Gutenberg University, 55122 Mainz, Germany., Wanker EE; Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany. Electronic address: ewanker@mdc-berlin.de.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2019 Jan 17; Vol. 26 (1), pp. 109-120.e7. Date of Electronic Publication: 2018 Nov 21.
DOI:	10.1016/j.chembiol.2018.10.013
Abstrakt:	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. (Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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