title: Stabilization, Assembly, and Toxicity of Trimers Derived from Aβ.
abstract: Oligomers of the β-amyloid peptide Aβ have emerged as important contributors to neurodegeneration in Alzheimer's disease. Mounting evidence suggests that Aβ trimers and higher-order oligomers derived from trimers have special significance in the early stages of Alzheimer's disease. Elucidating the structures of these trimers and higher-order oligomers is paramount for understanding their role in neurodegeneration. This paper describes the design, synthesis, X-ray crystallographic structures, and biophysical and biological properties of two stabilized trimers derived from the central and C-terminal regions of Aβ. These triangular trimers are stabilized through three disulfide cross-links between the monomer subunits. The X-ray crystallographic structures reveal that the stabilized trimers assemble hierarchically to form hexamers, dodecamers, and annular porelike structures. Solution-phase biophysical studies reveal that the stabilized trimers assemble in solution to form oligomers that recapitulate some of the higher-order assemblies observed crystallographically. The stabilized trimers share many of the biological characteristics of oligomers of full-length Aβ, including toxicity toward a neuronally derived human cell line, activation of caspase-3 mediated apoptosis, and reactivity with the oligomer-specific antibody A11. These studies support the biological significance of the triangular trimer assembly of Aβ β-hairpins and may offer a deeper understanding of the molecular basis of Alzheimer's disease.
authors.affiliation: Department of Chemistry, University of California, Irvine , Irvine, California 92697-2025, United States.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Kreutzer
authors.affiliation: Department of Chemistry, University of California, Irvine , Irvine, California 92697-2025, United States.
authors.forename: Stan
authors.initials: S
authors.lastname: Yoo
authors.affiliation: Department of Chemistry, University of California, Irvine , Irvine, California 92697-2025, United States.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Spencer
authors.affiliation: Department of Chemistry, University of California, Irvine , Irvine, California 92697-2025, United States.
authors.forename: James S
authors.identifier: 0000-0002-2273-1029
authors.initials: JS
authors.lastname: Nowick
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D010455:Peptides