Aggregation of the 42-mer amyloid beta peptide (A beta 42) plays a pivotal role in the pathogenesis of Alzheimer's disease. Recent investigations suggested the isomerization and/or racemization of Asp at position 1, 7, or 23 to be associated with the pathological role of A beta 42. Our previous study indicated that the turn at positions 22 and 23 of A beta 42 is closely related to its neurotoxicity through the formation of radicals. To clarify the contribution of these modifications at Asp23 to the pathology, three isomerized and/or racemized A beta 42 mutants were prepared. L-isoAsp23- and D-Asp23-A beta 42 showed moderate aggregative ability similar to the wild type. However, D-Asp23-A beta 42 was less neurotoxic than the wild type, while L-isoAsp23-A beta 42 was as toxic as the wild type. In contrast, D-isoAsp23-A beta 42 showed weak aggregative ability without neurotoxicity. These results suggest the isomerization and/or racemization of Asp23 not to be related to the pathogenesis, but to be a consequence of chemical reactions during the long-term deposition of fibrils. (c) 2007 Elsevier Inc. All rights reserved.