Alzheimer's disease is associated with the aggregation of the misfolded neuronal peptide, amyloid-β42 (Aβ42). Evidence has suggested that several reasons are responsible for the toxicity caused by the aggregation of Aβ42, including the conformational restriction of Aβ42. In this study, one of the toxic conformers of Aβ42, which contains a Glu-to-Pro substitution (E22P-Aβ42), was explored using atomic force microscopy and molecular docking to study the aggregation dynamics. We proposed a systematic model of fibril formation to better understand the molecular basis of conformational transitions in the Aβ42 species. Our results demonstrated the formation of amorphous aggregates in E22P-Aβ42 that are stem-based, network-like structures, while the formation of mature fibrils occurred in the less toxic conformer of Aβ42, E22-Aβ42, that are sphere-like flexible structures. A comparison was made between the biophysical properties of E22P-Aβ42 and E22-Aβ42 that revealed that E22P-Aβ42 had greater stiffness, dihedral angle, number of β sheets involved, and elasticity, compared with E22-Aβ42. These findings will have considerable implications toward our understanding of the structural basis of the toxicity caused by conformational diversity in Aβ42 species.
Keywords: amyloid-β42; atomic force microscopy; biophysical properties; fibril formation; molecular docking; oligomerization; toxic conformer (E22P-Aβ42).