Inhibition of amyloid Ab aggregation by high pressures or specific D-enantiomeric peptides

Author(s):Show less -

Cavini, Italo A. ^{[1, 2]} ; Munte, Claudia E. ^{[1, 2]} ; Erlach, Markus Beck ^[2] ; van Groen, Thomas ^[3] ; Kadish, Inga ^[3] ; Zhang, Tao ^{[4, 5]} ; Ziehm, Tamar ^[5] ; Nagel-Steger, Luitgard ^{[4, 5]} ; Kutzsche, Janine ^[5] ; Kremer, Werner ^[2] ; Willbold, Dieter ^{[4, 5]} ; Kalbitzer, Hans Robert ^[2]

Affiliation

^[1] Univ Sao Paulo, Phys Inst Sao Carlos, Sao Carlos, SP - Brazil

^[2] Univ Regensburg, Inst Biophys & Phys Biochem, Univ Str 31, D-93053 Regensburg - Germany

^[3] Univ Alabama Birmingham, Birmingham, AL 35294 - USA

^[4] Heinrich Heine Univ Dusseldorf, Inst Phys Biol & BMFZ, D-40225 Dusseldorf - Germany

^[5] Forschungszentrum Julich, Struct Biochem ICS 6, Inst Complex Syst, D-52425 Julich - Germany

• Document type: Journal article
• Source: CHEMICAL COMMUNICATIONS; v. 54, n. 26, p. 3294-3297, APR 4 2018.
• Web of Science Citations: 7

Abstract

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. (AU)

• FAPESP's process: 10/01362-5 - Interaction of proteins with lipidic microdomains and biological membrane models
• Grantee: Claudia Elisabeth Munte
• Support type: Regular Research Grants
• FAPESP's process: 13/04433-9 - Structure and dynamics of excited rare states of the Alzheimer's disease beta-amyloid peptide studied by high-pressure NMR
• Grantee: Italo Augusto Cavini
• Support type: Scholarships in Brazil - Doctorate (Direct)