Aggregation of the amyloid beta peptides, (Abeta1-42 and Abeta1-40) plays a pivotal role in pathogenesis of Alzheimer's disease. Although it is widely accepted that the aggregates of Abetas mainly consist of beta-sheet structure, the precise aggregation mechanism remains unclear. To identify amino acid residues that are important for the P-sheet formation, a series of proline-substituted mutants of Abeta1-42 peptides at positions 19-26 was synthesized in a highly pure form and their aggregation ability and neurotoxicity on PC12 cells were investigated. All proline-substituted Abeta1-42 mutants except for 22P-and 23P-Abeta1-42 were hard to aggregate and showed weaker cytotoxicity than wild-type Abeta1-42, suggesting that the residues at positions 19-21 and 24-26 are important for the beta-sheet formation. In contrast. 22P-Abeta1-42 extensively aggregated with stronger cytotoxicity than wild-type Abeta1-42. Since proline has a propensity for beta-turn Structure Lis a Pro-X corner, these data implicate that P-turn formation at positions 22 and 23 plays a crucial role in the aggregation and neutrotoxicity of Abeta peptides. (C) 2002 Elsevier Science (USA). All rights reserved.