Amyloid-beta (Ap) proteins, which consist of 42 amino acids (A beta(1-42) ), are the major constituent of neuritic plaques that form in the brains of senile patients with Alzheimer's disease (AD). Several reports state that three aspartic acid (Asp) residues at positions 1, 7, and 23 in A beta(1-42) in the plaques of patients with AD are highly isomerized from the to n-form. Using biophysical experiments, the present study shows that simultaneous o-isomerization of Asp residues at positions 7 and 23 (D-Asp(7,23)) enhances oligomerization, fibril formation, and neurotoxic effect of A beta(1-42) . In addition, o-isomerization of Asp at position 1 (D-Aspl) suppresses malignant effects induced by D-Asp(7,23) of A beta(1-42) . These results provide fundamental information to elucidate molecular mechanisms of AD pathogenesis and to develop potent inhibitors of amyloid aggregates and A beta neurotoxicity. (C) 2013 Elsevier Inc. All rights reserved.