title: Amyloid β Oligomeric Species Present in the Lag Phase of Amyloid Formation.
abstract: Alzheimer's disease (AD)-associated amyloid β peptide (Aβ) is one of the main actors in AD pathogenesis. Aβ is characterized by its high tendency to self-associate, leading to the generation of oligomers and amyloid fibrils. The elucidation of pathways and intermediates is crucial for the understanding of protein assembly mechanisms in general and in conjunction with neurodegenerative diseases, e.g., for the identification of new therapeutic targets. Our study focused on Aβ42 and its oligomeric assemblies in the lag phase of amyloid formation, as studied by sedimentation velocity (SV) centrifugation. The assembly state of Aβ during the lag phase, the time required by an Aβ solution to reach the exponential growth phase of aggregation, was characterized by a dominant monomer fraction below 1 S and a population of oligomeric species between 4 and 16 S. From the oligomer population, two major species close to a 12-mer and an 18-mer with a globular shape were identified. The recurrence of these two species at different initial concentrations and experimental conditions as the smallest assemblies present in solution supports the existence of distinct, energetically favored assemblies in solution. The sizes of the two species suggest an Aβ42 aggregation pathway that is based on a basic hexameric building block. The study demonstrates the potential of SV analysis for the evaluation of protein aggregation pathways.
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Centre Jülich, Jülich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wolff
authors.affiliation: Dep. of Molecular and Chemical Physics, Moscow Institute of Physics and Technology, Dolgoprudniy, Russian Federation.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Unuchek
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Centre Jülich, Jülich, Germany; Institute of Complex Systems, Neutron Scattering (ICS-1), Research Centre Jülich, Jülich, Germany.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Centre Jülich, Jülich, Germany; Dep. of Molecular and Chemical Physics, Moscow Institute of Physics and Technology, Dolgoprudniy, Russian Federation; Institut de Biologie Structurale J.-P. Ebel, Université Grenoble Alpes, Grenoble, France; Institut de Biologie Structurale J.-P. Ebel, Centre National de la Recherche Scientifique, Grenoble, France; Institut de Biologie Structurale J.-P. Ebel, Direction des Sciences du Vivant, Commissariat à l'Énergie Atomique, Grenoble, France.
authors.forename: Valentin
authors.initials: V
authors.lastname: Gordeliy
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Centre Jülich, Jülich, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Centre Jülich, Jülich, Germany.
authors.forename: Luitgard
authors.initials: L
authors.lastname: Nagel-Steger
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42)