The Kinetics and Thermodynamics of the Amyloid Beta Peptide

Amyloids are a category of protein structures where many individual polypeptide chains fold to form long β-sheet fibrils. These are strongly associated to many of today's incurable
and fatal diseases, such as Alzheimer's and Parkinson's disease. However, the exact cause of toxicity and disease initiation remains elusive. Amyloids are also interesting from a materials science perspective. Therefore, the goal of this thesis is to increase the understanding of the thermodynamic driving forces and mechanistic steps behind amyloid formation. Paper I presents a label-free high-throughput solubility assay to facilitate the study of amyloid proteins, the assay is applied to Aβ40 under a few different conditions. Paper II investigates
the temperature dependence of Aβ42 solubility, which shows a non-monotonic dependence, indicative of the hydrophobic effect being the thermodynamic driving force for fibril formation. Paper III examines the mechanistic effect of gentle agitation on the aggregation process of Aβ42 and finds that primary and secondary nucleation are responsible for the accelerated aggregation caused by gentle agitation. Paper IV presents an assay which classifies amyloid fibril morphs based on their seeding properties. With this assay, we find that fibrils formed at 60 and 70 °C have different properties than fibrils formed at 10 to 50 °C. Collectively, the tools and insights presented in this thesis contribute to fundamental science and may help the development of diagnostics, pharmaceuticals and new materials in the future.