Destruction of amyloid fibrils by graphene through penetration and extraction of peptides

Abstract

Current therapies for Alzheimer's disease (AD) can provide a moderate symptomatic reduction or delay progression at various stages of the disease, but such treatments ultimately do not arrest the advancement of AD. As such, novel approaches for AD treatment and prevention are urgently needed. We here provide both experimental and computational evidence that pristine graphene and graphene-oxide nanosheets can inhibit Aβ peptide monomer fibrillation and clear mature amyloid fibrils, thus impacting the central molecular superstructures correlated with AD pathogenesis. Our molecular dynamics simulations for the first time reveal that graphene nanosheets can penetrate and extract a large number of peptides from pre-formed amyloid fibrils; these effects seem to be related to exceptionally strong dispersion interactions between peptides and graphene that are further enhanced by strong π-π stacking between the aromatic residues of extracted Aβ peptides and the graphene surface. Atomic force microscopy images confirm these predictions by demonstrating that mature amyloid fibrils can be cut into pieces and cleared by graphene oxides. Thioflavin fluorescence assays further illustrate the detailed dynamic processes by which graphene induces inhibition of monomer aggregation and clearance of mature amyloid fibrils, respectively. Cell viability and ROS assays indicate that graphene oxide can indeed mitigate cytotoxicity of Aβ peptide amyloids. Our findings provide new insights into the underlying molecular mechanisms that define graphene-amyloid interaction and suggest that further research on nanotherapies for Alzheimer's and other protein aggregation-related diseases is warranted.

Contrasting effects of nanoparticle–protein attraction on amyloid aggregation

“…On the other hand, NPs such as graphene, graphene oxide nanosheets, carbon nanotubes and NiPAM:BAM co-polymeric NPs feature strong binding to Aβ peptides and thus strongly hindered amyloid aggregation of Aβ. 42,67,68 For example, in a recent study combining all-atom molecular dynamics and docking simulations with experimental characterizations, 69 the amyloid fibril formation of Aβ was found to be disrupted by a strong binding between peptides and graphene/graphene oxide nanosheets enhanced by π–π stacking between aromatic residues and the carbon-based NP surface. It has also been demonstrated that graphene oxide NPs strongly inhibited the formation of Aβ amyloid fibrils, 67 where the retardation/inhibition of amyloid fibril formation was revealed by both ThT fluorescence and AFM imaging.…”

Recent Advances in the Synthesis of Graphene-Based Nanomaterials for Controlled Drug Delivery

“…Finally, as most of studies are currently focused on the delivery of drug for cancer cells, it is possible to utilize graphene-based nanomaterials for the detection and therapy of other diseases such as Parkinson's, Alzheimer's, HIV, and others. For example, previously Yang and co-workers have reported that graphene could destruct the formation of amyloid fibrils [90], which provides a potential idea for designing graphene-based anti-Alzheimer's drugs.…”

Modulating protein amyloid aggregation with nanomaterials

“…84 Using molecular dynamics simulations Yang et al revealed that graphene nanosheets could penetrate and extract peptides from pre-formed amyloid fibrils. 52 Given extensive library of proteins identified within human circulation, current research related to NP-mediated regulation of amyloid fibrillization lacks data concerning the structure and aggregation of plasma proteins upon protein-NP interactions. 25,59,63,70,85 …”

“…Chem. 2014; 289, 31066-31076 51 ; Nanoscale 2015, 7 , 18725–18737 52 ; Small , 2016, 12 , 1615–1626, 53 copyright 2016 John Wiley & Sons.…”