Nanoprobing of the effect of Cu(2+) cations on misfolding, interaction and aggregation of amyloid ? peptide.

ABSTRACT: Misfolding and aggregation of the amyloid ?-protein (A?) are hallmarks of Alzheimer's disease. Both processes are dependent on the environmental conditions, including the presence of divalent cations, such as Cu(2+). Cu(2+) cations regulate early stages of A? aggregation, but the molecular mechanism of Cu(2+) regulation is unknown. In this study we applied single molecule AFM force spectroscopy to elucidate the role of Cu(2+) cations on interpeptide interactions. By immobilizing one of two interacting A?42 molecules on a mica surface and tethering the counterpart molecule onto the tip, we were able to probe the interpeptide interactions in the presence and absence of Cu(2+) cations at pH 7.4, 6.8, 6.0, 5.0, and 4.0. The results show that the presence of Cu(2+) cations change the pattern of A? interactions for pH values between pH 7.4 and pH 5.0. Under these conditions, Cu(2+) cations induce A?42 peptide structural changes resulting in N-termini interactions within the dimers. Cu(2+) cations also stabilize the dimers. No effects of Cu(2+) cations on A?-A? interactions were observed at pH 4.0, suggesting that peptide protonation changes the peptide-cation interaction. The effect of Cu(2+) cations on later stages of A? aggregation was studied by AFM topographic images. The results demonstrate that substoichiometric Cu(2+) cations accelerate the formation of fibrils at pH 7.4 and 5.0, whereas no effect of Cu(2+) cations was observed at pH 4.0. Taken together, the combined AFM force spectroscopy and imaging analyses demonstrate that Cu(2+) cations promote both the initial and the elongation stages of A? aggregation, but protein protonation diminishes the effect of Cu(2+).

SUBMITTER: Lv Z 

PROVIDER: S-EPMC3586772 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature