Distinct Early Folding and Aggregation Properties of Alzheimer Amyloid-β Peptides Aβ40 and Aβ42.

The amyloid β peptide (Aβ), composed of 40 or 42 amino acids, is a critical component in the etiology of the neurodegenerative Alzheimer disease. Aβ is prone to aggregate and forms amyloid fibrils progressively both in vitro and in vivo. To understand the process of amyloidogenesis, it is pivotal to examine the initial stages of the folding process. We examined the equilibrium folding properties, assembly states, and stabilities of the early folding stages of A1340 and A1342 prior to fibril formation. We found that Aβ40 and Aβ42 have different conformations and assembly states upon refolding from their unfolded ensembles. Aβ40 is predominantly an unstable and collapsed monomeric species, whereas Aβ42 populates a stable structured trimeric or tetrameric species at concentrations above ~12.5 µM. Thermodynamic analysis showed that the free energies of Aβ40 monomer and Aβ42 trimer/tetramer are ~1.1 and ~15/~22 kcal/mol, respectively. The early aggregation stages of Aβ40 and Aβ42 contain different solvent-exposed hydrophobic surfaces that are located at the sequences flanking its protease-resistant segment. The amyloidogenic folded structure of Aβ is important for the formation of spherical β oligomenic species. However, β oligomers are not an obligatory intermediate in the process of fibril formation because oligomerization is inhibited at concentrations of urea that have no effect on fibril formation. The distinct initial folding properties of Aβ40 and Aβ42 may play an important role in the higher aggregation potential and pathological significance of Aβ42. [ABSTRACT FROM AUTHOR]