Size Matters: A Mechanistic Model of Nanoparticle Curvature Effects on Amyloid Fibril Formation

Abstract

The aggregation of peptides into amyloid fibrils is linked to ageing-related diseases, such as Alzheimer's disease and type 2 diabetes. Interfaces, particularly those with large nanostructured surface areas, can affect the kinetics of peptide aggregation, ranging from a complete inhibition to strong acceleration. While a number of physiochemical parameters determine interface effects, we here focus on the role of nanoparticle curvature for the aggregation of the amyloidogenic peptides Aβ40, NNFGAIL, GNNQQNY and VQIYVK. Nanoparticles (NPs) provided a surface for peptide monomers to adsorb, enabling the nucleation into oligomers and fibril formation. High surface curvature, however, destabilized prefibrillar structures, providing an explanation for inhibitory effects on fibril growth. Thioflavin T (ThT) fluorescence assays as well as dynamic light scattering (DLS), atomic force microscopy (AFM) and electron microscopy experiments revealed NP size-dependent effects on amyloid fibril formation, with differences between the peptides. While 5 nm gold NPs (AuNP-5) retarded or inhibited the aggregation of most peptides, larger 20 nm gold NPs (AuNP-20) tended to accelerate peptide aggregation. Molecular dynamics (MD) studies demonstrated that NPs' ability to catalyze or inhibit oligomer formation was influenced by the oligomer stability at curved interfaces which was lower at more highly curved surfaces. Differences in the NP effects for the peptides resulted from the peptide properties (size, aggregation propensity) and concomitant surface binding affinities. The results can be applied to the design of future nanostructured materials for defined applications.

Influencing factors and characterization methods of nanoparticles regulating amyloid aggregation

“…67 From a dynamics viewpoint, larger-size NPs can provide an attractive surface for nucleated seeds, while smaller-size NPs can affect the structure of the original protofibril oligomers and interfere with the structure of the oligomers and protofibrils. 68 Moreover, the crowding effect of NPs increases with decreasing size, which can destabilize the β structure and thus inhibit amyloid aggregation. 69 From a thermodynamics viewpoint, larger NPs dominate the adsorption energy during the profibrotic stage, and the adsorption energy decreases with increasing size, inducing strong adsorption interactions to adjust the lag phase to promote amyloid fibrillation.…”

Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders—Denial is not an option

“…Particularly relevant to this study is the fact that UFPM/NPs are very effective in their capacity to aggregate, conglomerate, and produce protein folding, destabilization, and fibrillation (5,61,63,65,67,69,70,(79)(80)(81)(82). John et al (81) referred to large nanostructures of ≥20 nm affecting the kinetic peptide aggregation, thus size and shape matter. They also discussed how NPs serve as a surface for the adsorption of peptide monomers and facilitate nucleation to oligomers and fibril formation (81).…”

“…John et al (81) referred to large nanostructures of ≥20 nm affecting the kinetic peptide aggregation, thus size and shape matter. They also discussed how NPs serve as a surface for the adsorption of peptide monomers and facilitate nucleation to oligomers and fibril formation (81). Mohammad-Beigi et al (82) discussed how α-synuclein undergoes interactions with NPs and how these interactions can be prevented by the characteristics of the protein corona acquired during the exposure of NPs to serum proteins.…”