Graphene oxide inhibits hIAPP amyloid fibrillation and toxicity in insulin-producing NIT-1 cells

Abstract

Human islet amyloid polypeptide (hIAPP or amylin) aggregation is directly associated with pancreatic β-cell death and subsequent insulin deficiency in type 2 diabetes (T2D). Since no cure is currently available for T2D, it is of great benefit to devise new anti-aggregation molecules, which protect β-cells against hIAPP aggregation-induced toxicity. Engineered nanoparticles have been recently exploited as anti-aggregation nanomedicines. In this work, we studied graphene oxide (GO) nanosheets for their potentials for hIAPP aggregation inhibition by combining computational modeling, biophysical characterizations and cell toxicity measurements. Using discrete molecular dynamics (DMD) simulations and in vitro studies, we showed that GO exhibited an inhibitory effect on hIAPP aggregation. DMD simulations indicated that the strong binding of hIAPP to GO nanosheets was driven by hydrogen bonding and aromatic stacking and that the strong peptide-GO binding efficiently inhibited hIAPP self-association and aggregation on the nanosheet surface. Secondary structure changes of hIAPP upon GO binding derived from DMD simulations were consistent with circular dichroism (CD) spectroscopy measurements. Transmission electron microscopy (TEM) images confirmed the reduction of hIAPP aggregation in the presence of GO. Furthermore, we carried out a cell toxicity assay and found that these nanosheets protected insulin-secreting NIT-1 pancreatic β-cells against hIAPP-induced toxicity. Our multidisciplinary study suggests that GO nanosheets have the potential to be utilized as an anti-aggregation nanomedicine itself in addition to a biosensor or delivery vehicle for the mitigation of T2D progression.

Star Polymers Reduce Islet Amyloid Polypeptide Toxicity via Accelerated Amyloid Aggregation

“…These amyloids were characterized by a central nucleation “core”, ranging from smaller clusters of 50–150 nm to micrometers in diameter. Fibrils of low persistence (average of 891.9 nm compared with that of 2,885 ± 60 nm for the IAPP control 6,7 ) and contour length (<1,350 nm) were additionally observed radiating out from the core, forming the full stelliform structure of ∼0.5 μm in diameter for smaller cores and micrometers in diameter for larger cores with some macroscopic aggregates visible in solution (Figure 4A).…”

Distinct oligomerization and fibrillization dynamics of amyloid core sequences of amyloid-beta and islet amyloid polypeptide

“…DMD is a unique type of molecular dynamics algorithm with significantly enhanced sampling efficiency, which has been widely used by our group and other in studying protein folding 22 , aggregation 63 , small molecule/nanoparticle peptides interactions 10,64 . In DMD simulations, the inter-atomic interactions have similar components as conventional molecular mechanics force fields, but the potential functions are modeled by discrete step-wise functions mimicking the continuous potential functions.…”

Implications of peptide assemblies in amyloid diseases

“…Graphene oxide nanosheets displayed strong inhibition effects on IAPP aggregation and associated cytotoxicity because strong binding affinity rendered the peptides to bind with the nanosheets rather than between themselves. 225 OH-terminated polyamyloidoamine (PAMAM-OH) dendrimers inhibited IAPP aggregation and cytotoxicity, where the polymeric NPs encapsulated and stabilized monomeric IAPP in their hydrophobic interior (Fig. 10b).…”