Journal
CHEMICAL COMMUNICATIONS
Volume 54, Issue 26, Pages 3294-3297Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c8cc01458b
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Funding
- DFG [FOR 1997]
- Humboldt Society
- HFSPO
- FCI
- FAPESP [2010/01362-5, 2013/04433-9]
- HGF HVF and Portfolio
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Pressure can shift the polymer-monomer equilibrium of A beta, increasing pressure first leads to a release of A beta-monomers, surprisingly at pressures higher than 180 MPa repolymerization is induced. By high pressure NMR spectroscopy, differences of partial molar volumes Delta V-0 and compressibility factors Delta beta' of polymerization were determined at different temperatures. The D-enantiomeric peptides RD2 and RD2D3 bind to monomeric A beta with affinities substantially higher than those determined for fibril formation. By reducing the A beta concentration below the critical concentration for polymerization they inhibit the formation of toxic oligomers. Chemical shift perturbation allows the identification of the binding sites. The D-peptides are candidates for drugs preventing Alzheimer's disease. We show that RD2D3 has a positive effect on the cognitive behaviour of transgenic (APPSwDI) mice prone to Alzheimer's disease. The heterodimer complexes have a smaller Stokes radius than A beta alone indicating the recognition of a more compact conformation of A beta identified by high pressure NMR before.
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