AGGREGATION AND SECONDARY STRUCTURE OF SYNTHETIC AMYLOID BETA-A4 PEPTIDES OF ALZHEIMERS-DISEASE

The deposition of amyloid βA4 in the brain is a major pathological hallmark of Alzheimer's disease. Amyloid βA4 is a peptide composed of 42 or 43 amino acid residues. In brain, it appears in the form of highly insoluble, filamentous aggregates. Using synthetic peptides corresponding to the natural βA4 sequence as well as analog peptides, we demonstrate requirements for filament formation in vitro. We also determine aggregational properties and the secondary structure of βA4. A comparison of amino-terminally truncated βA4 peptides identifies a peptide spanning residues 10 to 43 as a prototype for amyloid βA4. Infrared spectroscopy of βA4 peptides in the solid state shows that their secondary structure consists of a β-turn flanked by two strands of antiparallel β-pleated sheet. Analog peptides containing a disulfide bridge were designed to stabilize different putative β-turn positions. Limited proteolysis of these analogs allowed a localization of the central β-turn at residues 26 to 29 of the entire sequence. Purified βA4 peptides are soluble in water. Size-exclusion chromatography shows that they form dimers that, according to circular dichroism spectroscopy, adopt a β-sheet conformation. Upon addition of salts, the bulk fraction of peptides precipitates and adopts a β-sheet structure. Only a small fraction of peptides remains solubilized. They are monomeric and adopt a random coil conformation. This suggests that the formation of aggregates depends upon a hydrophobic effect that leads to intra- and intermolecular interactions between hydrophobic parts of the βA4 sequence. This model is sustained by the properties of βA4 analogs in which hydrophobic residues were substituted. These peptides show a markedly increased solubility in salt solutions and have lost the ability to form filaments. In contrast, the substitution of hydrophilic residues leads only to small deviations in the shape of filaments, indicating that hydrophilic residues contribute to the specificity of interactions between βA4 peptides. © 1991.