Work with the Alzheimer's disease-related synthetic peptide beta-amyloid (Aβ) is a challenging task because of its disadvantageous dissolution properties and high propensity for aggregation. Recently, a new synthetic derivative, iso-Aβ42, has been introduced, which is a precursor of Aβ42, and it offers advantages as concerns its synthesis and use for sample preparation. These two Aβ forms showed high similarity in their biological effects, as well as in their main structural characteristics under well-chosen experimental circumstances. When we changed these conditions, considerable dissimilarities appeared in the aggregation properties of the two peptides. In the present study, the aggregation pathways of native and precursor-derived Aβ42 oligomers were compared in a physiological buffer with and without divalent metal ions (Ca2+/Mg2+). The presence of these ions influenced the Aβ conformations, the morphology as well as formation dynamics of aggregates in a different manner, as it was demonstrated by thioflavin-T-binding experiments, transmission electron microscopy and electronic circular dichroism measurements. Namely, the aggregation of native Aβ42 to fibrils was facilitated, while the aggregation of precursor-derived Aβ42 was hindered by these divalent metal ions. The observed differences in the aggregation had an impact also on the biological efficiency of native and precursor-derived Aβ42 as it was elucidated by viability assays with enhanced sensitivity on primary endothelial cell cultures. Using replica exchange molecular dynamics, we modeled the conformational ensembles of the two investigated Aβ variants evolving during preparation process. We found considerable differences in the probability distribution of the conformers that can explain the observed dissimilarities in their aggregation properties.
ASJC Scopus subject areas
- Condensed Matter Physics
- Physical and Theoretical Chemistry