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

摘要

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 40-100μm 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.