Yan Li-Mei, Velkova Aleksandra, Kapurniotu Aphrodite
Division of Peptide Biochemistry, Technische Universitat Munchen, Emil-Erlenmeyer-Forum 5, D- 85354 Freising, Germany.
Curr Pharm Des. 2014;20(8):1182-91. doi: 10.2174/13816128113199990064.
Increasing amounts of evidence suggest that Alzheimer's disease (AD) and type 2 diabetes (T2D) are linked to each other. We have recently identified in vitro a high affinity interaction between β-amyloid peptide (Aβ) of AD and islet amyloid polypeptide (IAPP) of T2D which results in the formation of non-fibrillar and non-cytotoxic Aβ-IAPP hetero-oligomers. The Aβ-IAPP interaction delays cytotoxic self-association of both polypeptides albeit it is unable to block it. In this context, IAPP-GI, a soluble conformationally constrained mimic of a non-amyloidogenic and non-toxic IAPP conformer, completely blocks Aβ amyloidogenesis and cytotoxicity. Here we studied the hetero-association pathways of Aβ with IAPP and with IAPP-GI. We found that preformed Aβ or IAPP fibrils and cytotoxic assemblies are able to seed amyloidogenesis and cytotoxicity in Aβ-IAPP but not in Aβ-IAPP-GI solutions. Initially non-fibrillar and non-toxic Aβ-IAPP but not Aβ-IAPP-GI hetero-oligomers were found to further aggregate into hetero-fibrils and cytotoxic assemblies in a process strongly enhanced under Aβ or IAPP self-assembly promoting conditions. Importantly, our studies provided evidence that initially non-fibrillar and non-toxic Aβ-IAPP hetero-oligomers are able to misfold into hetero-fibrils and indicated a crucial role of the strong amyloidogenic character of IAPP in this process. These results uncover a novel molecular property of the Aβ and IAPP sequences, i.e. their ability to form hetero-fibrils, and offer mechanistic support to a model linking Aβ and IAPP hetero-association to their cytotoxic self-association pathways and thus likely to the pathogenesis of AD and T2D.
越来越多的证据表明，阿尔茨海默病（AD）与2型糖尿病（T2D）相互关联。我们最近在体外鉴定出AD的β-淀粉样肽（Aβ）与T2D的胰岛淀粉样多肽（IAPP）之间存在高亲和力相互作用，这导致形成非纤维状且无细胞毒性的Aβ-IAPP异源寡聚体。Aβ-IAPP相互作用虽无法阻止两种多肽的细胞毒性自聚集，但会延迟其发生。在此背景下，IAPP-GI是一种非淀粉样生成且无毒的IAPP构象的可溶性构象受限模拟物，它能完全阻断Aβ淀粉样变和细胞毒性。在此，我们研究了Aβ与IAPP以及与IAPP-GI的异源缔合途径。我们发现，预先形成的Aβ或IAPP纤维以及细胞毒性聚集体能够引发Aβ-IAPP溶液中的淀粉样变和细胞毒性，但不能引发Aβ-IAPP-GI溶液中的这些过程。最初发现非纤维状且无毒的Aβ-IAPP而非Aβ-IAPP-GI异源寡聚体在Aβ或IAPP自组装促进条件下会强烈促进进一步聚集成异源纤维和细胞毒性聚集体。重要的是，我们的研究提供了证据，表明最初非纤维状且无毒的Aβ-IAPP异源寡聚体能够错误折叠成异源纤维，并表明IAPP强烈的淀粉样生成特性在这一过程中起关键作用。这些结果揭示了Aβ和IAPP序列的一种新分子特性，即它们形成异源纤维的能力，并为将Aβ和IAPP异源缔合与其细胞毒性自组装途径以及可能与AD和T2D发病机制联系起来的模型提供了机制支持。
