Low generation anionic dendrimers modulate islet amyloid polypeptide self-assembly and inhibit pancreatic β-cell toxicity†
The deposition of the islet amyloid polypeptide (IAPP) as insoluble amyloid fibrils in the pancreatic islets is associated with type II diabetes. Recent studies have revealed that pre-fibrillar proteospecies and/or the amyloidogenic process mediate β-cell degeneration whereas amyloid fibrils are poorly cytotoxic. Thus, therapeutic strategies that aim at preventing β-cell death associated with amyloid deposition should either sequester prefibrillar species and/or modulate the initial steps of fibrillization. In this view, low generation flexible dendritic scaffolds harboring 4 to 16 hydroxyl, amine, carboxylate or sulfate functional groups were designed and evaluated for their effects on IAPP self-assembly and cytotoxicity. Whereas neutral polyhydroxylated and polycationic dendrimers did not affect the kinetics of amyloid assembly, carboxylated dendrimers accelerated IAPP fibrillization proportionally to surface group density. Interestingly, as revealed by thioflavin T fluorescence, circular dichroism spectroscopy and atomic force microscopy, the G0 sulfated dendrimer inhibited amyloid formation by maintaining the peptide in a random coil conformation. In contrast, G1 sulfated dendrimers potentiated IAPP self-assembly into long amyloid fibrils by a scaffold-based mechanism. Anionic dendrimers attenuated IAPP-induced toxicity on pancreatic β-cells. Our results indicate that sulfated dendrimers can alter the fibrillization pathway of IAPP and inhibit its proteotoxicity, either by accelerating amyloid formation or by trapping the peptide in a non-aggregating and non-toxic state. This study offers novel mechanistic insights for the design of a nanomolecular scaffold to manipulate the self-assembly of natively disordered amyloidogenic peptides.
- This article is part of the themed collection: Towards understanding and treating Alzheimer’s disease