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RESEARCH PRODUCT
The Anti-amyloid Compound DO1 Decreases Plaque Pathology and Neuroinflammation-Related Expression Changes in 5xFAD Transgenic Mice
Nancy NeuendorfMiguel A. Andrade-navarroNicole GroenkeErich E. WankerDavid P. WolferEric BlancSigrid SchnoeglWilfried NietfeldChristian ErckElisabetta VannoniDieter BeuleChristian HaenigBeate FriedrichAnnett BoeddrichJulius Tachu BabilaHenrik MartensManuela JacobAlexander BuntruJochen C. MeierThomas WiglendaMaarten LoosLisa DiezMatthew R. Huskasubject
MaleGenetically modified mouse1303 BiochemistryAmyloid10017 Institute of AnatomyClinical BiochemistryMice TransgenicPlaque Amyloid610 Medicine & healthBiologyProtein aggregation1308 Clinical Biochemistry01 natural sciencesBiochemistryPolymerizationPathogenesisMiceProtein AggregatesStructure-Activity RelationshipAlzheimer DiseaseGene expressionDrug Discovery1312 Molecular BiologyAnimalsColoring AgentsMolecular BiologyNeuroinflammationInflammationPharmacologyAmyloid beta-PeptidesDose-Response Relationship DrugMolecular Structure010405 organic chemistry3002 Drug DiscoveryBrainSmall moleculeMolecular medicine0104 chemical sciencesCell biologyMice Inbred C57BL3004 Pharmacology10036 Medical Clinic1313 Molecular Medicine570 Life sciences; biologyMolecular MedicineFemaleAzo Compoundsdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-02-06 |