Dottorato in SCIENZE CHIMICHE

Titolo della tesi: Interaction Study of Prefibrillar Oligomers of Salmon Calcitonin with Cellular Model Membranes aimed to design Nanocarriers for Diagnosis and Cure of the Amyloid-related Diseases

The investigation of the amyloid proteins and the related diseases are one of the topics of the last decades. This family comprises several proteins found in most vertebrates performing different biological functions useful to the organism in their native state. However, when these undergo a misfolding, they are responsible for several diseases, of which those that arouse most attention are the neurodegenerative ones, such as Amyloid-β and tau proteins responsible for Alzheimer's disease (AD), or α-synuclein related to Parkinson's disease. Despite the differences in the sequences, these proteins follow the same aggregation pathway and seem to act similarly in causing the disorders, which is why a common mechanism has been hypothesized. Actually, the mechanisms of the harmful interaction with the target cells, together with the aggregate's structures responsible, are still under debate. The most relevant are the "pore hypothesis" involving the early amyloid aggregates, and the membrane disruption provoked by the final structures of the aggregation process, i.e. the fibers. Focusing on the AD, many molecules have been investigated for their protective or disaggregating effects. The major obstacle to cross is to obtain a significant bioavailability of the active drug inside the brain, therefore the development of nanocarriers performing this function is essential. In this work, the amyloid protein salmon Calcitonin (sCT) is used as a model to investigate the role of different aggregates and the mechanisms involved in membrane damage. The protein-membrane interaction studies are carried on the protein and the liposomes containing the fluorescent probe FLUO-4 and composed by DPPC, cholesterol and monosialoganglioside-GM1 in different proportion. In parallel, gold nanoparticles with mixed thiols exhibiting size and surface properties suitable for drug delivery purposes were synthetized and preliminary characterized.