Competitive homo- and hetero- self-assembly of amyloid-beta 1-42 and 1-40 in the early stage of fibrillation

Abstract

Amyloid-beta 1-42 (A beta 42) and 1-40 (A beta 40) peptides, whose self-assembly process has been linked with the formation of amyloid plaques in Alzheimer's disease, exist as a mixture in human fluids. For this reason, heteromeric self-assembly of A beta 42 and A beta 40 has been widely investigated to understand the influence of this mixture in A$ fibrillation. However, understanding the role of heteromeric self-assembly in A beta fibrillation is a challenge owing to the heterogeneous cross-interactions between A beta 42 and A beta 40. Herein, we demonstrated the influence of the cross-interaction of A beta 42 and A beta 40 in the early stage of fibrillation using electrospray ionization mass spectrometry (ESI-MS) and drift tube ion mobility spectrometry (DTIMS) along with solution small-angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations. In the mixture of A beta 42 and A beta 40, A beta 42 has only a slight preference for homo-oligomerization versus hetero-oligomerization with A beta 40 (similar to 1-2 fold) when forming small oligomers (from dimer to tetramer) in the early stage of fibrillation. However, the cross-interaction is gradually attenuated as oligomerization proceeds because of the different conformations in the A beta 42 and A beta 40 assemblies. Consequently, the competitive self-assembly of A beta 42 and A beta 40 can disturb the homo-oligomerization of A beta 42 in the early stage of fibrillation, whereas A beta 42 and A beta 40 species prefer the independent self-assembly after the early stage. (C) 2018 Elsevier B.V. All rights reserved.