Human pro-islet amyloid polypeptide (ProIAPP 1–48) forms amyloid fibrils and amyloid spherulites in vitro

Abstract

Deposition of β sheets of islet amyloid polypeptide (IAPP) in pancreatic tissue is implicated in the aetiology of type 2 diabetes mellitus (T2DM). IAPP is cleaved from its precursor protein, pro-islet amyloid polypeptide (ProIAPP) and incomplete cleavage results in ProIAPP 1–48, which is found co-deposited with IAPP. Cu(II) prevents IAPP from forming amyloid and herein we investigated if it would also prevent ProIAPP 1–48 from forming β sheets. Excess Cu(II) prevented ProIAPP 1–48 from forming amyloid and additionally reversed the formation of β sheets in pre-formed fibrils of the peptide. The latter was also true for ProIAPP 1–48 fibrils formed in the presence of Al(III). An unexpected finding was the formation of spherulites of ProIAPP 1–48 which were only observed in preparations which included Al(III). The spherulites were 40–100 μm in diameter and stained positively for Al(III) suggesting a role for this metal in their formation. The abolition by Cu(II) of the propensity of ProIAPP 1–48 to form amyloid may have important implications for the treatment of T2DM. The immediate significance for diabetes of the equally novel observation of spherulites of ProIAPP 1–48 is unknown though, as with spherulites of Aβ 42 in Alzheimer's disease, there may be implications for the aetiology of the disease.