Aromaticity of Phenylalanine Residues Is Essential for Amyloid Formation by Alzheimer's Amyloid β-Peptide

The abnormal aggregation of amyloid beta-peptide (A beta) is central to the pathogenesis of Alzheimer's disease, the major form of dementia. Aromatic pi-pi interactions have been suggested to play a crucial role in the aggregation of not only A beta, but also other amyloidogenic proteins. In this study, each or all phenylalanine (Phe) residues at the 4th, 19th, and 20th positions of A beta-(1-40) were substituted by hydrophobic cyclohexylalanine (Cha), which is sterically similar to Phe, but lacks pi-electrons, to reveal effects of interactions involving pi-electrons on the aggregation of A beta both in aqueous solution and GM1-containing membranes. We found that each Cha substitution significantly inhibited fibril formation by A beta, indicating a pivotal role of aromatic interactions. Furthermore, the A beta analog with three Cha residues effectively retarded the fibrillation of the wild-type A beta.