Distinct early folding and aggregation properties of Alzheimer amyloid-β peptides Aβ40 and Aβ42 -: Stable trimer or tetramer formation by Aβ42

The amyloid beta peptide (A beta), composed of 40 or 42 amino acids, is a critical component in the etiology of the neurodegenerative Alzheimer disease. A beta 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 A beta 40 and A beta 42 prior to fibril formation. We found that A beta 40 and A beta 42 have different conformations and assembly states upon refolding from their unfolded ensembles. A beta 40 is predominantly an unstable and collapsed monomeric species, whereas A beta 42 populates a stable structured trimeric or tetrameric species at concentrations above similar to 12.5 mu M. Thermodynamic analysis showed that the free energies of A beta 40 monomer and A beta 42 trimer/tetramer are similar to 1.1 and similar to 15/similar to 22kcal/mol, respectively. The early aggregation stages of A beta 40 and A beta 42 contain different solvent-exposed hydrophobic surfaces that are located at the sequences flanking its protease-resistant segment. The amyloidogenic folded structure of A beta is important for the formation of spherical beta oligomeric species. However, beta 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 A beta 40 and A beta 42 may play an important role in the higher aggregation potential and pathological significance of A beta 42.