CLVFFA-Functionalized Gold Nanoclusters Inhibit Aβ40 Fibrillation, Fibrils’ Prolongation, and Mature Fibrils’ Disaggregation

Abstract

The abnormal aggregation of amyloid beta (Aβ or A beta) from monomeric proteins into amyloid fibrils is an important pathological contact to Alzheimer’s disease (AD). Amyloid beta 40 (Aβ40), the pivotal biomarker of AD, aggregates to form amyloid plaques. For this reason, inhibition of amyloid fibrillation had become a crucial prevention and therapeutic strategy. Usually, LVFFA is the central hydrophobic fragment of Aβ and can inhibit the aggregation of Aβ40. In this work, in order to improve the inhibitory ability of LVFFA, hexapeptide CLVFFA were conjugated at the surface of Au clusters (AuNCs) to manufacture a nanosized inhibitor, AuNCs-CLVFFA. Thioflavin T fluorescence and transmission electron microscope results showed that AuNCs-CLVFFA inhibited Aβ40 fibrillogenesis, fibrils’ prolongation, and mature fibrils’ disaggregation. Furthermore, AuNCs as the backbone of the inhibitor showed extraordinary inhibition ability for Aβ40 aggregation at a low AuNCs-CLVFFA concentration. Free hexapeptide CLVFFA, at the same concentration, showed almost no inhibition. Additionally, the inhibitor could maintain the optical properties of nanoclusters, and the cell viability demonstrated that the inhibitor had good biocompatibility and may potentially be applied into AD therapy or treatment.

Nanomaterials for Modulating the Aggregation of β-Amyloid Peptides

“…Unlike AuNPs, gold nanoclusters (AuNCs) consist of several to dozens of atoms that have excellent optical properties of intense fluorescence and high photostability. As shown in Figure 3 B, Hao et al found that AuNCs modified with CLVFFA via Au-S bonds showed improved inhibitory ability [ 65 ]. The results exhibited that AuNCs-CLVFFA could block the fibrillogenesis of Aβ 1–40 and the prolongation of fibrils and disaggregate the mature fibrils into oligomers.…”

“…( B ) Schematic of CLVFFA-functionalized AuNCs for the inhibition of Aβ fibrillation. Reprinted with permission from reference [ 65 ]. Copyright 2019 American Chemical Society.…”

Nanochaperone‐Based Strategies to Control Protein Aggregation Linked to Conformational Diseases

“…[85] CLVFFA-conjugated gold nanoclusters inhibited Ab40 fibrillogenesis,f ibril prolongation, and disaggregated mature fibrils. [86] LPFFDfunctionalized AuNPs have shown synergistic effects in aggregation inhibition and fibril destabilization. [87,89] Tw o critical factors must be considered for surface functionalization with amyloid-recognizing peptides,n amely the use of charged residues to enhance colloidal stability and ag ood ability to adopt as econdary structure and consequently to interact with the protein.…”

“…LVFFARK‐functionalized NPs restricted Aβ42 conformational changes, redirected its aggregation into unstructured, off‐pathway aggregates and reduced Aβ toxicity [85] . CLVFFA‐conjugated gold nanoclusters inhibited Aβ40 fibrillogenesis, fibril prolongation, and disaggregated mature fibrils [86] . LPFFD‐functionalized AuNPs have shown synergistic effects in aggregation inhibition and fibril destabilization [87, 89] .…”

Amyloid ß-Targeted Inhibitory Peptides for Alzheimer’s Disease: Current State and Future Perspectives

“…The current inhibitory peptides have certain limitations such as poor BBB permeability and high cytotoxicity. To overcome these problems and further improve the inhibitory activity, a number of studies have focused on peptide-nanostructure conjugates (PNCs) approach that provides an opportunity to increase the capabilities of both these classes of materials (55,104,105). Nanostructures could be considered as a potential vehicle to overcome poor BBB permeability and bring hope for neurodegenerative diseases therapy due to their size and various surface modifications (106).…”