Dual effect of PEG-PE micelle over the oligomerization and fibrillation of human islet amyloid polypeptide

Xiaocui Fang,Qunxing Huang,Chen Wang,Yanlian Yang,Maryam Yousaf

doi:10.1038/s41598-018-22820-w

Abstract

The oligomerization and fibrillation of human islet amyloid polypeptide (hIAPP) play a central role in the pathogenesis of type 2 diabetes. Strategies for remodelling the formation of hIAPP oligomers and fibrils have promising application potential in type 2 diabetes therapy. Herein, we demonstrated that PEG-PE micelle could inhibit hIAPP oligomerization and fibrillation through blocking the hydrophobic interaction and the conformational change from random coil to β-sheet structures of hIAPP. In addition, we also found that PEG-PE micelle could remodel the preformed hIAPP fibrils allowing the formation of short fibrils and co-aggregates. Taken together, PEG-PE micelle could rescue hIAPP-induced cytotoxicity by decreasing the content of hIAPP oligomers and fibrils that are related to the oxidative stress and cell membrane permeability. This study could be beneficial for the design and development of antiamyloidogenic agents.

Highlights

The deposition of insoluble amyloid aggregates, formed due to misfolding of proteins and peptides, is involved in the pathogenesis of many amyloidogenic diseases including Parkinson’s disease (PD), Huntington’s disease (HD), Alzheimer’s disease (AD), mad cow disease, and type 2 diabetes (T2DM)[1,2,3]
To determine whether polyethylene glycol (PEG)-PE micelle can act as an inhibitor for both hIAPP1-37 and hIAPP8-37 aggregation, the aggregation kinetics of hIAPP1-37 and hIAPP8-37 were monitored by measuring ThT fluorescence intensity
These results of ThT binding assay indicated that the aggregation of both hIAPP1-37 and hIAPP8-37 were consistent with a typical nucleation-growth mode[25]

Summary

Introduction

The deposition of insoluble amyloid aggregates, formed due to misfolding of proteins and peptides, is involved in the pathogenesis of many amyloidogenic diseases including Parkinson’s disease (PD), Huntington’s disease (HD), Alzheimer’s disease (AD), mad cow disease, and type 2 diabetes (T2DM)[1,2,3]. Extensive studies have shown that the deposition of hIAPP amyloid is associated with pancreatic β-cell dysfunction and loss of β-cell mass, which is the main cause of T2DM pathogenesis[6,10] In this regard, inhibitors targeting hIAPP aggregates hold great application potential. Our previous studies have demonstrated that PEG-PE micelle could assist non-native insulin refolding into its native states and inhibit insulin aggregation through blocking hydrophobic interactions of dithiothreitol (DTT)-denatured insulin A and B chains[20] This prompted us whether PEG-PE micelle could remodel hIAPP assembly and rescue hIAPP-induced cytotoxicity. This work will broaden the application of PEG-PE as an antiamyloidogenic agent

Methods

Results

Conclusion