title: Inhibition of Aβ(1-40) fibril formation by cyclophilins.
abstract: Cyclophilins interact directly with the Alzheimer's disease peptide Aβ (amyloid β-peptide) and are therefore involved in the early stages of Alzheimer's disease. Aβ binding to CypD (cyclophilin D) induces dysfunction of human mitochondria. We found that both CypD and CypA suppress in vitro fibril formation of Aβ(1-40) at substoichiometric concentrations when present early in the aggregation process. The prototypic inhibitor CsA (cyclosporin A) of both cyclophilins as well as the new water-soluble MM258 derivative prevented this suppression. A SPOT peptide array approach and NMR titration experiments confirmed binding of Aβ(1-40) to the catalytic site of CypD mainly via residues Lys(16)-Glu(22) The peptide Aβ(16-20) representing this section showed submicromolar IC50 values for the peptidyl prolyl cis-trans isomerase activity of CypD and CypA and low-micromolar KD values in ITC experiments. Chemical cross-linking and NMR-detected hydrogen-deuterium exchange experiments revealed a shift in the populations of small Aβ(1-40) oligomers towards the monomeric species, which we investigated in the present study as being the main process of prevention of Aβ fibril formation by cyclophilins.
authors.affiliation: Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle (Saale), Germany.
authors.forename: Marten
authors.initials: M
authors.lastname: Villmow
authors.affiliation: Institute of Physics, Biophysics, Martin Luther University Halle-Wittenberg, Betty-Heimann-Straße 7, D-06120 Halle (Saale), Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle (Saale), Germany Department of Enzymology, Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Weinbergweg 22, D-06120 Halle (Saale), Germany.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Malesevic
authors.affiliation: Institute of Physics, Biophysics, Martin Luther University Halle-Wittenberg, Betty-Heimann-Straße 7, D-06120 Halle (Saale), Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Sachs
authors.affiliation: Martin Luther University Halle-Wittenberg, Biocenter, Weinbergweg 22, D-06120 Halle (Saale), Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Hause
authors.affiliation: Institute for Pharmaceutical Biotechnology, Ulm University, Helmholtzstraße 8/1, D-89081 Ulm, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fändrich
authors.affiliation: Institute of Physics, Biophysics, Martin Luther University Halle-Wittenberg, Betty-Heimann-Straße 7, D-06120 Halle (Saale), Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Balbach
authors.affiliation: Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle (Saale), Germany Department of Enzymology, Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Weinbergweg 22, D-06120 Halle (Saale), Germany cordelia.schiene-fischer@biochemtech.uni-halle.de.
authors.forename: Cordelia
authors.initials: C
authors.lastname: Schiene-Fischer
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D021984:Cyclophilin A / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000081406:Peptidyl-Prolyl Isomerase F; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D016572:Cyclosporine; D021984:Cyclophilin A; D021983:Cyclophilins
keywords: Alzheimer's disease peptide; Aβ(1–40); CypD; amyloid fibrils; cyclophilin