MOLECULAR DETERMINANTS OF AMYLOID DEPOSITION IN ALZHEIMERS-DISEASE - CONFORMATIONAL STUDIES OF SYNTHETIC BETA-PROTEIN FRAGMENTS

The amyloid 0-protein (1–42) is a major constituent of the abnormal extracellular amyloid plaque that characterizes the brains of victims of Alzheimer’s disease. Two peptides, with sequences derived from the previously unexplored C-terminal region of the 0-protein, 026–33 (H2N-SNKGAIIG-CO2H) and β34-42 (H2N-LMVGGVVIA-CO2H), were synthesized and purified, and their solubility and conformational properties were analyzed. Peptide β26-33 was found to be freely soluble in water; however, peptide β34-42 was virtually insoluble in aqueous media, including 6 M guanidinium thiocyanate. The peptides formed assemblies having distinct fibrillar morphologies and different dimensions as observed by electron microscopy of negatively stained samples. X-ray diffraction revealed that the peptide conformation in the fibrils was cross-β. A correlation between solubility and 0-structure formation was inferred from FTIR studies: β26-33, when dissolved in water, existed as a random coil, whereas the water-insoluble peptide β34-42 possessed antiparallel β-sheet structure in the solid state. Solubilization of β34-42 in organic media resulted in the disappearance of β-structure. These data suggest that the sequence 34–42, by virtue of its ability to form unusually stable β-structure, is a major contributor to the insolubility of the β-protein and may nucleate the formation of the fibrils that constitute amyloid plaque. © 1990, American Chemical Society. All rights reserved.