Self-assembly of amyloid-β peptides (Aβ) has accepted as an important issue, because the final product of the self-assembly (i.e. amyloid fibrils) is highly relevant to the Alzheimer’s disease (AD). Among various Aβ alloforms, Aβ 1-42 (Aβ42) and Aβ 1-40 (Aβ40) are mainly involved in Aβ fibril formation. The self-assembly mechanisms of Aβ42 and Aβ40 are known to be different and Aβ42 and Aβ40 can form hetero-assemblies through their cross-interaction. However, the role of hetero-assemblies of a mixture of Aβ42 and Aβ40 is not yet fully understood. Thus, characterizing the cross-interaction between Aβ42 and Aβ40 is crucial for understanding the role of hetero-assemblies during the fibrillation of mixed Aβ peptides. In this research, we demonstrated the influence of the cross-interaction of Aβ42 and Aβ40 in the early stage of fibrillation. We monitored the fibrillation process of Aβ42, Aβ40 and their 1:1 mixtures using thioflavin T (ThT) assay and electrospray ionization mass spectrometry (ESI-MS). Then, we further investigated the preference for homo- and hetero- oligomerization of Aβ40 and Aβ42 using ion mobility spectrometry (IMS) along with solution small-angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations. Our results suggest that the competitive self-assembly of Aβ42 and Aβ40 plays a pivotal role in disturbing homo-oligomerization of Aβ42 in the early stage of fibrillation. |