Modulation of amyloid β peptide self-assembly: Aggregation mechanisms associated with Alzheimer's disease

Self-assembly of the amyloid β peptide (Aβ) is strongly linked to the pathogenesis of Alzheimer's disease. Modulation of this aggregation process by small molecule compounds has been shown to potentially inhibit or redirect this process. Thus, a detailed understanding of the mechanism of action of such aggregation modulators is crucial for speci c design of therapeutics against amyloidosis diseases. The interaction of small molecules, such as lacmoid, Congo red or surfactants, and Aβ have been investigated in this licentiate thesis using a broad range of biophysical techniques. Here, we characterize the formation and exchange kinetics of soluble dynamic co-aggregates that are formed by Aβ and the aggregation modulators. Alongside a slow brillation process of Aβ in the time scale of minutes to hours, dynamic exchange between free and co-aggregate bound peptide occurs on a much faster time scale (microto milli-seconds). Depending on the di erent conformational preferences of Aβ, aggregation may be promoted or inhibited. β-structure promoting compounds, e.g. surfactants at intermediate concentrations, facilitate bril formation. In contrast, when Aβ adopts a mainly unstructured state in the co-aggregate, as in the presence of lacmoid, transient interactions with free peptide can kinetically redirect Aβ from aggregation. Based on these ndings, the molecular mechanism of action of Aβ in the presence of aggregation modulators can be rationalized in terms of exchange and aggregation rates and conformational preferences. Licentiate thesis Axel Abelein