Amyloid-β 1–42 (Aβ42) and 1–40 (Aβ40) 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 Aβ42 and Aβ40 has been widely investigated to understand the influence of this mixture in Aβ fibrillation. However, understanding the role of heteromeric self-assembly in Aβ fibrillation is a challenge owing to the heterogeneous cross-interactions between Aβ42 and Aβ40. Herein, we demonstrated the influence of the cross-interaction of Aβ42 and Aβ40 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 Aβ42 and Aβ40, Aβ42 has only a slight preference for homo-oligomerization versus hetero-oligomerization with Aβ40 (∼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 Aβ42 and Aβ40 assemblies. Consequently, the competitive self-assembly of Aβ42 and Aβ40 can disturb the homo-oligomerization of Aβ42 in the early stage of fibrillation, whereas Aβ42 and Aβ40 species prefer the independent self-assembly after the early stage.
- Alzheimer's disease
- Drift tube ion mobility spectrometry
- Electrospray ionization-mass spectrometry
- Solution small-angle X-ray scattering
ASJC Scopus subject areas
- Condensed Matter Physics
- Physical and Theoretical Chemistry