title: Design and Characterization of Chemically Stabilized Aβ42 Oligomers.
abstract: A popular working hypothesis of Alzheimer's disease causation is amyloid β-protein oligomers are the key neuropathogenetic agents. Rigorously elucidating the role of oligomers requires the production of stable oligomers of each size. We previously used zero-length photochemical cross-linking to allow stabilization, isolation, and determination of structure-activity relationships of pure populations of Aβ40 dimers, trimers, and tetramers. We also attempted to study Aβ42 but found that Aβ42 oligomers subjected to the same procedures were not completely stable. On the basis of the fact that Tyr is a critical residue in cross-linking chemistry, we reasoned that the chemical accessibility of Tyr10 in Aβ42 must differ from that in Aβ40. We thus chemically synthesized four singly substituted Tyr variants that placed the Tyr in different positions across the Aβ42 sequence. We then studied the stability of the resulting cross-linked oligomers as well as procedures for fractionating the oligomers to obtain pure populations of different sizes. We found that [Phe(10),Tyr(42)]Aβ42 produced stable oligomers yielding highly pure populations of dimers through heptamers. This provides the means to establish formal structure-activity relationships of these important Aβ42 assemblies. In addition, we were able to analyze the dissociation patterns of non-cross-linked oligomers to produce a model for oligomer formation. This work is relevant to the determination of structure-activity relationships that have the potential to provide mechanistic insights into disease pathogenesis.
authors.affiliation: Department of Radiology, School of Medicine, University of California , San Diego, California 92093, United States.|Department of Neurology, David Geffen School of Medicine at UCLA , Los Angeles, California 90095, United States.
authors.forename: Ghiam
authors.initials: G
authors.lastname: Yamin
authors.affiliation: Department of Neurology, School of Medicine, Washington University at St. Louis , St. Louis, Missouri 63110, United States.
authors.forename: Tien-Phat Vuong
authors.initials: TP
authors.lastname: Huynh
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA , Los Angeles, California 90095, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D003432:Cross-Linking Reagents; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000235:genetics; D015202:Protein Engineering; D055550:Protein Stability; D020836:Protein Structure, Quaternary
chemical_list: D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D064267:Intrinsically Disordered Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)