title: Formation of dynamic soluble surfactant-induced amyloid β peptide aggregation intermediates.
abstract: Intermediate amyloidogenic states along the amyloid β peptide (Aβ) aggregation pathway have been shown to be linked to neurotoxicity. To shed more light on the different structures that may arise during Aβ aggregation, we here investigate surfactant-induced Aβ aggregation. This process leads to co-aggregates featuring a β-structure motif that is characteristic for mature amyloid-like structures. Surfactants induce secondary structure in Aβ in a concentration-dependent manner, from predominantly random coil at low surfactant concentration, via β-structure to the fully formed α-helical state at high surfactant concentration. The β-rich state is the most aggregation-prone as monitored by thioflavin T fluorescence. Small angle x-ray scattering reveals initial globular structures of surfactant-Aβ co-aggregated oligomers and formation of elongated fibrils during a slow aggregation process. Alongside this slow (minutes to hours time scale) fibrillation process, much faster dynamic exchange (k(ex) ∼1100 s(-1)) takes place between free and co-aggregate-bound peptide. The two hydrophobic segments of the peptide are directly involved in the chemical exchange and interact with the hydrophobic part of the co-aggregates. Our findings suggest a model for surfactant-induced aggregation where free peptide and surfactant initially co-aggregate to dynamic globular oligomers and eventually form elongated fibrils. When interacting with β-structure promoting substances, such as surfactants, Aβ is kinetically driven toward an aggregation-prone state.
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius Väg 16, SE-106 91 Stockholm, Sweden.
authors.forename: Axel
authors.initials: A
authors.lastname: Abelein
authors.forename: Jørn Døvling
authors.initials: JD
authors.lastname: Kaspersen
authors.forename: Søren Bang
authors.initials: SB
authors.lastname: Nielsen
authors.forename: Grethe Vestergaard
authors.initials: GV
authors.lastname: Jensen
authors.forename: Gunna
authors.initials: G
authors.lastname: Christiansen
authors.forename: Jan Skov
authors.initials: JS
authors.lastname: Pedersen
authors.forename: Jens
authors.initials: J
authors.lastname: Danielsson
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Otzen
authors.forename: Astrid
authors.initials: A
authors.lastname: Gräslund
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D008956:Models, Chemical; D010446:Peptide Fragments / Q000737:chemistry*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D013501:Surface-Active Agents / Q000737:chemistry*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D013501:Surface-Active Agents; C078592:amyloid beta-protein (1-40)
keywords: Aggregation; Alzheimer Disease; Amyloid; Amyloid β Peptide; Circular Dichroism (CD); NMR; NMR Relaxation Dispersion; Small Angle X-ray Scattering; Surfactant