Aggregated beta-amyloid peptides (A beta) are neurotoxic and responsible for neuronal death both in vitro and in vivo. From the structural point of view, A beta self-aggregation involves a conformational change in the peptide. Here, we investigated the relationship between conformational changes and amino acid residues of A beta(40). Urea unfolding in combination with NMR spectroscopy was applied to probe the stabilization of A beta(40) conformation. L17 and F19 residues were found more sensitive to environmental changes than the other residues. Replacement of these two residues with alanine could stabilize the conformation of A beta(40). Further analysis indicated that the A beta(40)(L17A/F19A) mutant could diminish the aggregation and reduce the neurotoxicity. These results suggest that L17 and F19 are the critical residues responsible for conformational changes which may trigger neurotoxic cascade of A beta(40). (c) 2011 Elsevier Inc. All rights reserved.