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

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