Baghel Divya, Ghosh Ayanjeet
Department of Chemistry and Biochemistry, The University of Alabama, 1007E Shelby Hall, Tuscaloosa, Alabama 35487, United States.
J Phys Chem Lett. 2024 Dec 12;15(49):12197-12205. doi: 10.1021/acs.jpclett.4c02827. Epub 2024 Dec 3.
Amyloid aggregates are hallmarks of the pathology of a wide range of diseases, including type 2 diabetes (T2D) and Alzheimer's disease (AD). Much epidemiological and pathological evidence points to significant overlap between AD and T2D. Individuals with T2D have a higher likelihood of developing AD; moreover, colocalized aggregates of amyloid β (Aβ) and the islet amyloid polypeptide (IAPP), the two main peptides implicated in the formation of toxic amyloid aggregates in AD and T2D, have also been identified in the brain. However, how these peptides interact with each other is not well understood, and the structural facets of heterotypic mixed fibrils formed via such interactions remain elusive. Here we use atomic force microscopy augmented with infrared spectroscopy to probe the secondary structure of individual aggregates formed via heterotypic interactions of Aβ and IAPP and provide unequivocal direct evidence of mixed aggregates. Furthermore, we show that co-aggregation of the peptides from the monomeric stage leads to the formation of unique polymorphs, in which both peptides undergo structural deviation from their native states, whereas seeding with preformed IAPP fibrils leads to aggregates similar to native Aβ. These findings highlight how heterotypic interactions between amyloidogenic peptides can lead to polymorphic diversity proteinopathies.
淀粉样聚集体是包括2型糖尿病（T2D）和阿尔茨海默病（AD）在内的多种疾病病理学的标志。大量流行病学和病理学证据表明AD和T2D之间存在显著重叠。患有T2D的个体患AD的可能性更高；此外，淀粉样β蛋白（Aβ）和胰岛淀粉样多肽（IAPP）的共定位聚集体也已在大脑中被发现，这两种主要肽与AD和T2D中有毒淀粉样聚集体的形成有关。然而，这些肽如何相互作用尚不清楚，通过这种相互作用形成的异型混合纤维的结构方面仍然难以捉摸。在这里，我们使用结合红外光谱的原子力显微镜来探测通过Aβ和IAPP的异型相互作用形成的单个聚集体的二级结构，并提供混合聚集体的确切直接证据。此外，我们表明，从单体阶段开始的肽的共聚集会导致形成独特的多晶型物，其中两种肽都会发生与其天然状态不同的结构偏差，而用预先形成的IAPP纤维进行接种会导致形成类似于天然Aβ的聚集体。这些发现突出了淀粉样生成肽之间的异型相互作用如何导致多晶型多样性蛋白病。
