Cyclophilins directly interact with the Alzheimer peptide Aβ and are therefore involved in the early stages of the Alzheimer disease. Aβ binding to cyclophilin D (CypD) 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 during the aggregation process. The prototypic inhibitor cyclosporin A (CsA) 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 K16-E22. The peptide Aβ(16-20) representing this section showed submicromolar IC50 values for the peptidyl-prolyl isomerase activity of CypD and CypA and low micromolar KD values in ITC experiments. Chemical cross-linking and NMR detected H/D exchange experiments revealed a shift of populations of small Aβ(1-40) oligomers towards the monomeric species, which we address to the main process of prevention of Aβ fibril formation by the here studied cyclophilins.
- Alzheimer peptide
- amyloid fibrils
- ©2016 The Author(s)
This is an Accepted Manuscript; not the final Version of Record. Archiving permitted only in line with the archiving policy of Portland Press Limited. All other rights reserved.