Aggregation and neurotoxicity of mutant amyloid β (Aβ) peptides with proline replacement: importance of turn formation at positions 22 and 23

Abstract

Aggregation of the amyloid β peptides (Aβ1-42 and Aβ1-40) plays a pivotal role in pathogenesis of Alzheimer's disease. Although it is widely accepted that the aggregates of Aβs mainly consist of β-sheet structure, the precise aggregation mechanism remains unclear. To identify amino acid residues that are important for the β-sheet formation, a series of proline-substituted mutants of Aβ1-42 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 Aβ1-42 mutants except for 22P- and 23P-Aβ1-42 were hard to aggregate and showed weaker cytotoxicity than wild-type Aβ1-42, suggesting that the residues at positions 19–21 and 24–26 are important for the β-sheet formation. In contrast, 22P-Aβ1-42 extensively aggregated with stronger cytotoxicity than wild-type Aβ1-42. Since proline has a propensity for β-turn structure as a Pro-X corner, these data implicate that β-turn formation at positions 22 and 23 plays a crucial role in the aggregation and neurotoxicity of Aβ peptides.