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Protein misfolding has been identified as the underlying molecular process found in several devastating neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease (AD/PD). Based on the aggregation behavior, the surface of AD and PD-associated amyloid fibrils has been suggested to act as a catalyzer for self-replication and generation of toxic oligomers. Specifically tailored molecular chaperones, such as the BRICHOS protein domain, were shown to bind to the amyloid fibrils and break this autocatalytic cycle, possibly by blocking specific aggregation hotspots on the fibrils surface.Here, we aim to elucidate structural features of these catalytic sites from diverse in vitro and in vivo-derived amyloid fibrils using an integrated approach of high-resolution techniques. This information will provide a detailed understanding of the generic molecular mechanisms of chaperone-amyloid interactions, which will open the possibility to specifically target aggregation hotspots by designer chaperones or other drugs. Other goals are to explore the potential of BRICHOS to transport biologic drugs over the blood-brain barrier (BBB), and to determine the seeding activity of samples from patients suffering from different neurodegenerative disorders, which could establish new diagnostic tools.