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 beta (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 beta-sheet formation is essential for the neurotoxicity of amyloid beta (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 beta protein.