Role of the region 23-28 in Abeta fibril formation: insights from simulations of the monomers and dimers of Alzheimer's peptides Abeta40 and Abeta42.

Self-assembly of the 40/42 amino acid Abeta peptide is a key player in Alzheimer's disease. Abeta40 is the most prevalent species, while Abeta42 is the most toxic. It has been suggested that the amino acids 21-30 could nucleate the folding of Abeta monomer and a bent in this region could be the rate-limiting step in Abeta fibril formation. In this study, we review our current understanding of the computer-predicted conformations of amino acids 23-28 in the monomer of Abeta(21-30) and the monomers Abeta40 and Abeta42. On the basis of new simulations on dimers of full-length Abeta, we propose that the rate-limiting step involves the formation of a multimeric beta-sheet spanning the central hydrophobic core (residues 17-21).