Epidemiological evidence shows an increased risk for developing Alzheimer’s disease in people affected by diabetes, a pathology associated with increased hyperglycemia. A potential factor that could explain this link could be the role that sugars may play in both diseases under the form of glycation. Contrary to glycosylation, glycation is an enzyme-free reaction that leads to formation of toxic advanced glycation end-products (AGEs). In diabetes, the islet amyloid polypeptide (IAPP or amylin) is found to be heavily glycated and to form toxic amyloid-like aggregates, similar to those observed for the Aβ peptides, often also heavily glycated, observed in Alzheimer patients. Here, we studied the effects of glycation on the structure and aggregation properties of IAPP with several biophysical techniques ranging from fluorescence to circular dichroism, mass spectrometry and atomic force microscopy. We demonstrate that glycation occurs exclusively on the N-terminal lysine leaving the only arginine (Arg11) unmodified. At variance with recent studies, we show that the dynamical interplay between glycation and aggregation affects the structure of the peptide, slows down the aggregation process and influences the aggregate morphology.

流行病学证据表明，患有糖尿病的人患阿尔茨海默氏病的风险增加，糖尿病是一种与高血糖升高相关的病理学。可以解释这种联系的一个潜在因素可能是糖以糖化形式在这两种疾病中发挥的作用。与糖基化相反，糖化是一种无酶反应，会导致有毒的晚期糖基化终产物 (AGE) 的形成。在糖尿病中，胰岛淀粉样多肽（IAPP 或胰淀素）被发现严重糖化并形成有毒的淀粉样蛋白样聚集物，类似于在阿尔茨海默病患者中观察到的 Aβ 肽，通常也是严重糖化的。在这里，我们利用荧光、圆二色性、质谱和原子力显微镜等多种生物物理技术研究了糖化对 IAPP 结构和聚集特性的影响。我们证明糖化仅发生在 N 末端赖氨酸上，仅留下精氨酸 (Arg11) 未修饰。与最近的研究不同的是，我们表明糖化和聚集之间的动态相互作用会影响肽的结构，减慢聚集过程并影响聚集体形态。