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Formation of dynamic soluble surfactant-induced amyloid β peptide aggregation intermediates
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 32, 23518-23528 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2013. Vol. 288, no 32, 23518-23528 p.
National Category
Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
URN: urn:nbn:se:su:diva-98634DOI: 10.1074/jbc.M113.470450ISI: 000330598200056PubMedID: 23775077OAI: oai:DiVA.org:su-98634DiVA: diva2:684709
Available from: 2014-01-08 Created: 2014-01-08 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Modulation of Alzheimer's amyloid β peptide self-assembly: Insights into molecular mechanisms of peptide aggregation associated with Alzheimer's disease
Open this publication in new window or tab >>Modulation of Alzheimer's amyloid β peptide self-assembly: Insights into molecular mechanisms of peptide aggregation associated with Alzheimer's disease
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Misfolding of proteins and peptides is closely linked to several neurodegenerative disorders, among them Alzheimer's disease (AD), the most prominent example of brain diseases. The self-assembly of the amyloid β peptide (Aβ) into amyloid fibrils is one histologic hallmark of AD. A detailed knowledge about the underlying mechanism(s) of Aβ aggregation is crucial for advances toward a fundamental understanding of the disease, which may promote the search for and design of efficient therapeutics. The work presented in this thesis deals with modulation of the aggregation process by various compounds, i.e. small organic molecules (e.g. lacmoid and Congo red), surfactants and metal ions. These results provide insight into the molecular mechanism of modulator interactions and interference with Aβ and its aggregation pathways. Applying a combination of kinetic and dynamic studies as well as structural investigations we characterized the molecular interactions between Aβ and aggregation modulators in terms of microscopic rate constants, conformational preferences and thermodynamics. An important conclusion is that these modulators form highly dynamic complexes with Aβ, with life-times on the timescale of milliseconds. Despite the similar exchange dynamics, the effect on peptide aggregation is modulator-specific and fibril formation can be accelerated, retarded or inhibited by their interactions. In summary, Aβ self-assembly is governed by microscopic kinetic and dynamic processes that can be altered by aggregation modulators. Further elucidation of these mechanisms is beneficial for the understanding and therapeutic intervention of amyloid diseases.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2015
National Category
Biophysics
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-114172 (URN)978-91-7649-104-1 (ISBN)
Public defence
2015-03-27, Magnéli hall, Arrhenius Laboratory, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2015-03-05 Created: 2015-02-23 Last updated: 2015-04-09Bibliographically approved
2. Modulation of amyloid β peptide self-assembly: Aggregation mechanisms associated with Alzheimer's disease
Open this publication in new window or tab >>Modulation of amyloid β peptide self-assembly: Aggregation mechanisms associated with Alzheimer's disease
2013 (English)Licentiate thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2013. 22 p.
National Category
Biophysics
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-89078 (URN)
Presentation
2013-04-09, Magnéli hall, 14:30 (English)
Opponent
Supervisors
Available from: 2013-04-10 Created: 2013-04-10 Last updated: 2015-02-23Bibliographically approved

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