title: Molecular determinants of amyloid deposition in Alzheimer's disease: conformational studies of synthetic beta-protein fragments.
abstract: The amyloid beta-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 beta-protein, beta 26-33 (H2N-SNKGAIIG-CO2H) and beta 34-42 (H2N-LMVGGVVIA-CO2H), were synthesized and purified, and their solubility and conformational properties were analyzed. Peptide beta 26-33 was found to be freely soluble in water; however, peptide beta 34-42 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-beta. A correlation between solubility and beta-structure formation was inferred from FTIR studies: beta 26-33, when dissolved in water, existed as a random coil, whereas the water-insoluble peptide beta 34-42 possessed antiparallel beta-sheet structure in the solid state. Solubilization of beta 34-42 in organic media resulted in the disappearance of beta-structure. These data suggest that the sequence 34-42, by virtue of its ability to form unusually stable beta-structure, is a major contributor to the insolubility of the beta-protein and may nucleate the formation of the fibrils that constitute amyloid plaque.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139.
authors.forename: K
authors.initials: K
authors.lastname: Halverson
authors.forename: P E
authors.initials: PE
authors.lastname: Fraser
authors.forename: D A
authors.initials: DA
authors.lastname: Kirschner
authors.forename: P T
authors.initials: PT
authors.lastname: Lansbury
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000032:analysis* / Q000648:ultrastructure; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D000682:Amyloid