The Anti-amyloid Compound DO1 Decreases Plaque Pathology and Neuroinflammation-Related Expression Changes in 5xFAD Transgenic Mice.
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.
Pubmed ID: 30472115 RIS Download
Research resources used in this publication
- R Project for Statistical Computing (RRID:SCR_001905) (software resource)
- Ingenuity Pathway Analysis (RRID:SCR_008653) (pathway analysis tool)
- LIMMA (RRID:SCR_010943) (software resource)
- B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (RRID:MMRRC_034840-JAX) (organism)
- B6SJLF1/J (RRID:IMSR_JAX:100012) (organism)
- Ingenuity Pathway Analysis (RRID:SCR_008653) (pathway analysis tool)
- LIMMA (RRID:SCR_010943) (software resource)
- R Project for Statistical Computing (RRID:SCR_001905) (software resource)
- Anti-Mouse IgG (Fc specific)-Peroxidase antibody produced in goat (RRID:AB_257867) (antibody)
- Anti-beta-Amyloid, 1-16 (RRID:AB_2565327) (antibody)
- Mouse IgG1 Isotype Control (RRID:AB_2532935) (antibody)
- Anti-GFAP (RRID:AB_887720) (antibody)
- B6SJLF1/J (RRID:IMSR_JAX:100012) (organism)
- Peroxidase-AffiniPure Goat Anti-Rabbit IgG (H+L) (min X Hu,Ms,Rat Sr Prot) (RRID:AB_2307391) (antibody)
- Peroxidase-AffiniPure Goat Anti-Mouse IgG (H+L) (min X Hu,Bov,Hrs,Rb,Sw Sr Prot) (RRID:AB_2307392) (antibody)
- AffiniPure Goat Anti-Mouse IgG (H+L) (min X Hu,Bov,Hrs Sr Prot) (RRID:AB_2338452) (antibody)
- Goat anti-Mouse IgG (H+L) Cross-Adsorbed ReadyProbes Secondary Antibody, Alexa Fluor™ 488 (RRID:AB_2556548) (antibody)
- B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (RRID:MMRRC_034840-JAX) (organism)
- Anti-GFAP (RRID:AB_2232308) (antibody)
- Anti-Amyloid Fibrils OC (RRID:AB_1977024) (antibody)
- Anti-beta-Amyloid, 17-24 (RRID:AB_2565324) (antibody)
Additional research tools detected in this publication
Antibodies used in this publication
- Peroxidase-AffiniPure Goat Anti-Rabbit IgG (H+L) (min X Hu,Ms,Rat Sr Prot) (RRID:AB_2307391)
- Anti-Mouse IgG (Fc specific)-Peroxidase antibody produced in goat (RRID:AB_257867)
- Anti-Amyloid Fibrils OC (RRID:AB_1977024)
- Anti-GFAP (RRID:AB_887720)
- Anti-GFAP (RRID:AB_2232308)
- Goat anti-Mouse IgG (H+L) Cross-Adsorbed ReadyProbes Secondary Antibody, Alexa Fluor™ 488 (RRID:AB_2556548)
- Anti-beta-Amyloid, 17-24 (RRID:AB_2565324)
- Peroxidase-AffiniPure Goat Anti-Mouse IgG (H+L) (min X Hu,Bov,Hrs,Rb,Sw Sr Prot) (RRID:AB_2307392)
- Mouse IgG1 Isotype Control (RRID:AB_2532935)
- AffiniPure Goat Anti-Mouse IgG (H+L) (min X Hu,Bov,Hrs Sr Prot) (RRID:AB_2338452)
- Anti-beta-Amyloid, 1-16 (RRID:AB_2565327)
Associated grants
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This is a list of tools and resources that we have found mentioned in this publication.
GraphPad Prism (tool)
RRID:SCR_002798
Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
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RRID:AB_2307391
This polyclonal targets Rabbit IgG (H+L)
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RRID:AB_257867
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RRID:AB_1977024
This polyclonal targets Amyloid Fibrils
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RRID:AB_2556548
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This isotype control targets Not Applicable
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RRID:AB_2565327
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RRID:SCR_001905
Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.
View all literature mentionsIngenuity Pathway Analysis (pathway analysis tool)
RRID:SCR_008653
A web-based software application that enables users to analyze, integrate, and understand data derived from gene expression, microRNA, and SNP microarrays, metabolomics, proteomics, and RNA-Seq experiments, and small-scale experiments that generate gene and chemical lists. Users can search for targeted information on genes, proteins, chemicals, and drugs, and build interactive models of experimental systems. IPA allows exploration of molecular, chemical, gene, protein and miRNA interactions, creation of custom molecular pathways, and the ability to view and modify metabolic, signaling, and toxicological canonical pathways. In addition to the networks and pathways that can be created, IPA can provide multiple layering of additional information, such as drugs, disease genes, expression data, cellular functions and processes, or a researchers own genes or chemicals of interest.
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RRID:SCR_010943
Software package for the analysis of gene expression microarray data, especially the use of linear models for analyzing designed experiments and the assessment of differential expression.
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RRID:MMRRC_034840-JAX
Mus musculus with name B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax from MMRRC.
View all literature mentionsB6SJLF1/J (organism)
RRID:IMSR_JAX:100012
Mus musculus with name B6SJLF1/J from IMSR.
View all literature mentionsIngenuity Pathway Analysis (pathway analysis tool)
RRID:SCR_008653
A web-based software application that enables users to analyze, integrate, and understand data derived from gene expression, microRNA, and SNP microarrays, metabolomics, proteomics, and RNA-Seq experiments, and small-scale experiments that generate gene and chemical lists. Users can search for targeted information on genes, proteins, chemicals, and drugs, and build interactive models of experimental systems. IPA allows exploration of molecular, chemical, gene, protein and miRNA interactions, creation of custom molecular pathways, and the ability to view and modify metabolic, signaling, and toxicological canonical pathways. In addition to the networks and pathways that can be created, IPA can provide multiple layering of additional information, such as drugs, disease genes, expression data, cellular functions and processes, or a researchers own genes or chemicals of interest.
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RRID:SCR_010943
Software package for the analysis of gene expression microarray data, especially the use of linear models for analyzing designed experiments and the assessment of differential expression.
View all literature mentionsR Project for Statistical Computing (software resource)
RRID:SCR_001905
Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.
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RRID:AB_257867
This polyclonal targets Mouse IgG (Fc specific)-Peroxidase antibody produced in goat
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RRID:AB_2565327
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RRID:AB_2532935
This isotype control targets Not Applicable
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RRID:IMSR_JAX:100012
Mus musculus with name B6SJLF1/J from IMSR.
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RRID:AB_2307391
This polyclonal targets Rabbit IgG (H+L)
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RRID:AB_2307392
This polyclonal targets Mouse IgG (H+L)
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RRID:AB_2338452
This unknown targets Mouse IgG (H+L)
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RRID:AB_2556548
This polyclonal secondary targets IgG (H+L)
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RRID:MMRRC_034840-JAX
Mus musculus with name B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax from MMRRC.
View all literature mentionsAnti-Amyloid Fibrils OC (antibody)
RRID:AB_1977024
This polyclonal targets Amyloid Fibrils
View all literature mentionsAnti-beta-Amyloid, 17-24 (antibody)
RRID:AB_2565324
This monoclonal targets beta-Amyloid 17-24
View all literature mentions
