Inhibition of amyloid peptide fibrillation by inorganic nanoparticles: functional similarities with proteins

Abstract

Aggregation of amyloid-β peptides (Aβ) into fibrils is the key pathological feature of many neurodegenerative disorders. Typical drugs inhibit Aβ fibrillation by binding to monomers in 1:1 ratio and display low efficacy. Here, we report that model CdTe nanoparticles (NPs) can efficiently prevent fibrillation of Aβ associating with 100–330 monomers at once. The inhibition is based on the binding multiple Aβ oligomers rather than individual monomers. The oligomer route of inhibition is associated with strong van der Waals interactions characteristic for NPs and presents substantial advantages in the mitigation of toxicity of the misfolded peptides. Molar efficiency and the inhibition mechanism revealed by NPs are analogous to those found for proteins responsible for prevention of amyloid fibrillation in human body. Besides providing a stimulus for finding biocompatible NPs with similar capabilities, these data suggest that inorganic NPs can mimic some sophisticated biological functionalities of proteins.

Figure 1

(A) Molecular structure of CdTe NPs and Aβ_1-42 peptide. Some of the molecules of TGA adsorbed to the surface of CdTe are removed for clarity. Peptide is folded in the configuration characteristic for fibrils. Molecular modeling was carried out by SPARTAN. (B) Kinetics of Aβ_1-40 fibrillation with and without CdTe NPs. Time-dependent ThT fluorescence was monitored at 485 nm with excitation wavelength of 450 nm. The molar ratio of [CdTe]/[Aβ_1-40] was varied from 0 to 0.005: (a) 0, (b) 0.001, (c), 0.005, (d), 0.01 and (e) 0.05. Fluorescence intensity of ThT at 485 nm is proportional to the amount of fibrils.

Figure 2

TEM (a – j) and AFM (k – o) images of Aβ_1-40 incubated with and without CdTe NPs. The molar ratios of [CdTe]/[Aβ_1-40] were (a, f, k) 0, (b, g, l) 0.001, (c, h, m) 0.005, (d, i, n) 0.01, and (e, j, o) 0.05. In TEM images, NPs appeared as bright spots that can be easily distinguished from the fibrils even for small concentrations of NPs. The Z-contrast nature of the images enables the direct visualization of the peptide structures without a staining process.

Figure 3

NMR spectra (a, b) and Western blot (c) with and without CdTe NPs. (a) 2D SOFAST-HMQC spectra of freshly dissolved Aβ_1-40 with increasing amounts of CdTe NPs at 10° C; (b) The change in the signal-to-noise ratio of Aβ_1-40; (c) Western blot of freshly prepared Aβ_1-42 (lane 1), 1 day incubated Aβ_1-42 in the absence (lane 2) and presence (lane 3) of CdTe NPs. In Western blotting, the molar ratio of [CdTe]/[Aβ_1-42] was 0.05. Notations for 1-letter abbreviation of each residue can be found in SI Text.

Figure 4

(A) FT-IR spectra of Aβ_1-42 with and without CdTe NPs. (a) CdTe NPs, (b – d) Aβ_1-42 with CdTe NPs. The molar ratios of [CdTe]/[Aβ_1-42] were (b) 0, (c) 0.01, and (d) 0.05. (B) CD spectra of Aβ_1-42 with and without CdTe NPs. The molar ratios of [CdTe]/[Aβ_1-42] were (a) 0, (b) 0.01, and (c) 0.05. Both FT-IR and CD spectra were obtained after 1 day incubation. In Figure 4B trace c, CD signal below ~ 215 nm became noisy by the strong absorbance of CdTe NPs.