Role of the region 23-28 in Aβ fibril formation:: Insights from simulations of the monomers and dimers of Alzheimer's peptides Aβ40 and Aβ42

Self-assembly of the 40/42 amino acid A beta peptide is a key player in Alzheimer's disease. A beta 40 is the most prevalent species, while A beta 42 is the most toxic. It has been suggested that the amino acids 21-30 could nucleate the folding of A beta monomer and a bent in this region could be the rate-limiting step in A beta fibril formation. In this study, we review our current understanding of the computer-predicted conformations of amino acids 23-28 in the monomer of A beta(21-30) and the monomers A beta 40 and A beta 42. On the basis of new simulations on dimers of full-length A beta, we propose that the rate-limiting step involves the formation of a multimeric beta-sheet spanning the central hydrophobic core ( residues 17-21).