Formation of Dynamic Soluble Surfactant-induced Amyloid β Peptide Aggregation Intermediates

• Published in: The Journal of biological chemistry Vol. 288; no. 32; pp. 23518 - 23528
• Main Authors: Abelein, Axel, Kaspersen, Jørn Døvling, Nielsen, Søren Bang, Jensen, Grethe Vestergaard, Christiansen, Gunna, Pedersen, Jan Skov, Danielsson, Jens, Otzen, Daniel E., Gräslund, Astrid
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.08.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Aggregation; Alzheimer Disease; Amyloid; Amyloid - chemistry; Amyloid beta-Peptides - chemistry; Amyloid β Peptide; Animals; biofysik; Biophysics; Circular Dichroism (CD); Models, Chemical; Molecular Biophysics; NMR; NMR Relaxation Dispersion; Peptide Fragments - chemistry; Protein Structure, Quaternary; Protein Structure, Secondary; Small Angle X-ray Scattering; Surface-Active Agents - chemistry; Surfactant; Aggregation; NMR; Amyloid β Peptide; Small Angle X-ray Scattering; Circular Dichroism (CD); Amyloid; NMR Relaxation Dispersion; Alzheimer Disease; Surfactant
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M113.470450

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 (kex ∼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. Background: β-Structured oligomers of the amyloid β peptide are considered neurotoxic and on-pathway to amyloid fibril formation. Results: Surfactant-induced co-aggregated oligomers show dynamic rapid exchange with free peptide during a slow fibril formation process. Conclusion: β-Structure inducing small molecules kinetically promote peptide assembly into co-aggregates. Significance: Knowledge about molecular mechanisms of peptide aggregation modulators is potentially helpful for therapeutic purposes.