The influence of aluminium and copper upon the early aggregatory behaviour and size of Islet amyloid polypeptide under simulated physiological conditions

Abstract

Background and aim: Islet amyloid polypeptide/amylin deposition in the form of amyloid plaques is a common pathological feature observed in the pancreatic tissue of those with Type II Diabetes Mellitus. Its propensity to form amyloid fibrils and the resultant toxicity of this peptide in vivo is influenced by both the concentration and species of metal present in situ. Herein, we examine the influence of Al (III) and Cu (II), applied at equimolar and supra-stoichiometric concentrations on the initial aggregatory behaviour of amylin under near physiological conditions.

Methods: Dynamic light scattering measurements, which monitored the aggregation status and size of the peptide in real time, were performed during the early lag-phase of fibrillogenesis (T ≤ 30 min) in the absence or presence of metal ions.

Results: Islet amyloid polypeptide (10 µM) rapidly aggregated when introduced into a physiological medium favouring the formation of large, agglomerated structures (> 1000 nm) after 30 min incubation. Neither the addition of equimolar or excess metals significantly influenced the size of the peptide when intensity distributions were consulted; however, number distributions indicated that both Al (III) and Cu (II) may have had, an albeit temporary, stabilising influence upon the conformations present within solution.

Conclusion: These results infer that small oligomeric species are likely transient entities that are rapidly incorporated into large agglomerates during the very initial stages of fibrillogenesis. While both Al (III) and Cu (II) both inhibited agglomeration to some degree, their stabilising affect upon peptide aggregation was limited over the juncture of the experiments performed herein; hence, it is difficult to say whether these metal ions play a role in enhancing the toxicity of these peptides through influencing their aggregation in the short-term.

Keywords: Aluminium; Amyloid; Diabetes Mellitus (type II); Dynamic light scattering; Peptide aggregation.