| Abstract [eng] |
Millions of people around the world suffer from amyloid-related disorders. Alzheimer’s disease alone afflicts more than 50 million patients worldwide. Despite continuous efforts, there are still no disease modifying drugs available for the majority of amyloid related disorders and the overall failure rate in clinical trials is very high. One of the main reasons for this is a lack of fundamental knowledge of amyloid fibril formation process. In the present work, aggregation processes of insulin, mouse prion protein and amyloid-beta were studied. Herein it is demonstrated that monomer-oligomer equilibrium is the fundamental factor governing the formation of distinct insulin fibril strains. Moreover, evidence of the possible direct role of oligomeric insulin forms in the amyloid fibril formation mechanism is provided. Also, in this work it is shown that environmental conditions define the inhibitory efficiency of anti-amyloid compounds in a very sensitive manner. Furthermore, new mechanistic insights into the processes of prion self-replication are presented. In particular, the fundamental role of secondary nucleation in the "strain switching" is demonstrated, and a new phenomenon, which emerges during self-propagation reaction of distinct prion strains under different environmental conditions, is described. Finally, herein it is demonstrated that high-resolution atomic force microscopy combined with microfluidic sample deposition platform enables the possibility to image all molecular species present during the aggregation time-course, and allows to acquire single-molecule quantitative data. |
