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)
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.
Research subject Biophysics
IdentifiersURN: urn:nbn:se:su:diva-114172ISBN: 978-91-7649-104-1OAI: oai:DiVA.org:su-114172DiVA: diva2:790119
2015-03-27, Magnéli hall, Arrhenius Laboratory, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Bax, Adriaan, Prof.
Gräslund, Astrid, Prof.
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.2015-03-052015-02-232015-04-09Bibliographically approved
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