Journal
ACS CHEMICAL NEUROSCIENCE
Volume 10, Issue 12, Pages 4800-4809Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.9b00458
Keywords
Alzheimer's disease; amyloid-beta protein; all-D-enantiomeric peptide; complex formation; nucleation
Funding
- Portfolio Technology and Medicine, the Helmholtz-Validierungsfonds of the Impulsand Vernetzungs-Fonds der Helmholtzgemeinschaft
- Portfolio Drug Research of the Impuls-and Vernetzungs-Fonds der Helmholtzgemeinschaft
- China Scholarship Council (CSC)
- iGRASPseed program of the HeinrichHeine-Universitat Dusseldorf
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The aggregation of amyloid-beta (A beta) into oligomers and fibrillary structures is critical for the pathogenesis of Alzheimers disease (AD). Recently, research effort has been focused on developing novel agents that can preferentially suppress A beta oligomer mediated toxicities, for example, by directly targeting these toxic assemblies. The compound RD2 has been developed and optimized for A beta 42 monomer binding and stabilization of the monomer in its native intrinsically disordered conformation. It has been demonstrated to improve and even reverse the cognitive and behavioral deficits in AD mouse models, while the detailed mechanism of action is not fully clarified. Here we focused on exploring the interaction between RD2 and A beta 42 monomers and its consequences for the fibrillation of A beta 42. RD2 binds to A beta 42 monomers with nanomolar affinities, according to microscale thermophoresis and surface plasmon resonance measurements. Complexes between RD2 and A beta 42 monomers are formed at 1:1 and other stoichiometries, as revealed by analytical ultracentrifugation. At substoichiometric levels, RD2 slows down the secondary structure conversion of A beta 42 and significantly delays the fibril formation. Our research provides experimental evidence in supporting that RD2 eliminates toxic A beta assemblies by stabilizing A beta monomers in their native intrinsically disordered conformation. The study further supports the promising application of RD2 in counteracting A beta aggregation related pathologies.
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