Correlation among Secondary Structure, Amyloid Precursor Protein Accumulation, and Neurotoxicity of Amyloid β(25–35) Peptide as Analyzed by Single Alanine Substitution

Structure-neurotoxicity relationships of amyloid β(25–35) peptide were studied by replacing each amino acid with Ala. In contrast to the general tendency in hydrophobicity-toxicity relationships, replacement of Asn27 yielded a more hydrophobic but less toxic analog and that of Met35 gave a less hydrophobic but more toxic one. Sedimentation profiles and CD spectra indicated that peptide aggregation via intermolecular β- sheet formation is essential for the neurotoxicity of amyloid β(25–35) peptide. The correlation between neurotoxicity and amyloid precursor protein accumulation suggested that the latter is one of the pathways of the neuronal death caused by amyloid β protein.