Major constituents of the amyloid plaques found in the brain of Alzheimer's patients are the 39-43 residue beta-amyloid (A beta) peptides. Extensive in vitro as well as in vivo biochemical studies have shown that the 40- and 42-residue A beta peptides play major roles in the neurodegenerative pathology of Alzheimer's disease. Although the two A beta peptides share common aggregation properties, the 42-residue peptide is more amyloidogenic and more strongly associated with amyloid pathology. Thus, characterizations of the two A beta peptides are of critical importance in understanding the molecular mechanism of A amyloid formation. In this report, we present combined CD and NMR studies of the monomeric states of the two peptides under both non-amyloidogenic (< 5 degrees C) and amyloid-forming conditions (> 5 degrees C) at physiological pH. Our CD studies of the A beta peptides showed that initially unfolded A beta peptides at low temperature (< 5 degrees C) gradually underwent conformational changes to more beta-sheet-like monomeric intermediate states at stronger amyloidogenic conditions (higher temperatures). Detailed residue-specific information on the structural transition was obtained by using NMR spectroscopy. Residues in the N-terminal (3-12) and 20-22 regions underwent conformational changes to more extended structures at the stronger amyloidogenic conditions. Almost identical structural transitions of those residues were observed in the two A beta peptides, suggesting a similar amyloidogenic intermediate for the two peptides. The 42-residue A beta (1-42) peptide was, however, more significantly structured at the C-terminal region (39-42), which may lead to the different aggregation propensity of the two peptides. (c) 2006 Elsevier Inc. All rights reserved.