Copper is a potent inhibitor of the propensity for human ProIAPP1-48 to form amyloid fibrils in vitro

Abstract

Abstract: Background: The amyloidogenic peptides IAPP and ProIAPP1-48 are implicated in β cell death in type 2 diabetes mellitus. While the mechanism of their deposition in vivo is unknown we have shown that in vitro metals can both accelerate, for example Al(III), and inhibit, for example Cu(II), their formation of amyloid. Methods: We have used a combination of thioflavin T fluorescence (ThT) and transmission electron microscopy (TEM) to investigate the potency with which Cu(II) prevented human ProIAPP1-48 from forming β sheets of amyloid fibrils both in the absence and presence of significant molar excesses of Al(III) or Zn(II). Results: Cu(II) prevented ProIAPP1-48 from forming fibrillar materials with β sheet structure at all concentrations above equimolar to peptide. At equimolar Cu(II) to ProIAPP1-48 fibrillar-like materials were observed by TEM though these were not ThT-positive. Significant excesses of the competitive metals Al(III) and Zn(II) were unable to influence these effects of Cu(II). Conclusions: Cu(II) was shown to be a potent inhibitor of amyloid formation by ProIAPP1-48 and its potency was unaffected by significant excesses of either Al(III) or Zn(II). If the propensities for IAPP and ProIAPP to form amyloid are central to the aetiology of cell death in type 2 diabetes mellitus then the availability of Cu(II) to prevent amyloidogenesis may be a critical factor for future therapy.