The interaction between CypD and Aβ(1-40) in mitochondria was described to lead to increased intracellular stress and finally to apoptosis of the cells. Here the biophysical and biochemical properties of the interaction between cyclophilins and Aβ(1-40) or related peptides, respectively, were investigated. Both, cyclophilin A (CypA) and CypD, suppress the Aβ(1-40) fibril formation at substoichiometric concentrations which was shown using the Thioflavin T assay for amyloid fibril detection. These results were confirmed by TEM analysis. SPOT peptide array analysis and HSQC-NMR studies identified Aβ(16-20) as the key region of the cyclophilin - Aβ(1-40) interaction. The pentapeptide (KLVFF) representing the sequence of Aβ(16-20) is capable to inhibit the peptidyl proly cis/trans isomerase activity of CypA and CypD in nanomolar concentrations. The tight binding cyclophilin inhibitor cyclosporine A (CsA) itself and the solubility improved CsA derivative MM258 could reverse the inhibitory effect of fibril formation by CypA and CypD. These findings indicate that the active sites of CypA and CypD are involved in the interaction. HSQC-NMR studies and PICUP (photo-induced cross-linking of unmodified proteins) experiments showed that CypA as well as CypD interact with early Aβ(1-40) species in the fibril formation process, presumably monomeric Aβ(1-40) species. New Mexico NMR studies suggest the suppression of β-sheet structure formation in Aβ(1-40) as a key mechanism of amyloid fibril formation inhibition by CypD.