Human pro-islet amyloid polypeptide (ProIAPP1-48) forms amyloid fibrils and amyloid spherulites in vitro

Deposition of beta 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 beta sheets. Excess Cu(II) prevented ProIAPP(1-48) from forming amyloid and additionally reversed the formation of beta sheets in pre-formed fibrils of the peptide. The latter was also true for ProIAPP(1-48) fibrils formed in the presence of AI(III). An unexpected finding was the formation of spherulites of ProIAPP(1-48) which were only observed in preparations which included AI(III). The spherulites were 40-100 mu m in diameter and stained positively for AI(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 A beta(42) in Alzheimer's disease, there may be implications for the aetiology of the disease. (c) 2010 Elsevier Inc. All rights reserved.