De Santis, Augusta (2018) Effect of polyunsaturated fatty acids on the structure and dynamics of lipid bilayers and on the interaction with peptides. [Tesi di dottorato]

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DocosaHexaenoic Acid (DHA) is the longest and most unsaturated fatty acid in cell membranes, associated to a numerous health benefits above all in pathological conditions such as Alzheimer’s disease and other neurodegenerative processes. DHA was proposed to alter the physicochemical features of the membrane, once converted to phospholipids, and/or to segregate cholesterol molecules in liquid ordered domains (Lo), typically associated to the lipid rafts. However, their mechanism of action is still elusive. With the aim to understand the functional role of DHA, we investigate the influence of different phospholipid containing this fatty acid, the 1-stearoyl-2-docosahexanoyl-glycerophosphocholine, SDPC, and the 1,2-docosahexanoyl-glycerophosphocholine, DDPC, embedded in lipid membranes composed by pure 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and in combination with Cholesterol (Chol), because they are characterized by different liquid crystalline mesostructures (e.g., ordered, Lo, vs. disordered, Ld). A combination of different physico-chemical techniques, in particular Electron Spin Resonance (ESR) spectroscopy and Neutron Reflectivity (NR), was used. Moving from the characterization of the lipid systems, we attempt to rationalize the DHA-phospholipids effect, in particular, the DDPC, on peptide/lipid interaction, focusing on the role played in amyloidogenic processes. Through a combined ESR and Circular Dichroism (CD) approach, the interaction of model membranes, containing DDPC, with different amyloidogenic peptides have been investigated. Two novel short amyloidogenic peptides derived from nucleophosmin-1 (NPM-1), a nucleolar protein with a likely involvement in Huntington Disease and Amyloid Leukaemia, corresponding to helix H2 and the N-terminal extended H2, Nterm, regions of NPM1 have been chosen. Then, the work has been scaled up to more biomimetic lipid membrane containing DDPC, to study the interaction with peptide hallmark of Alzheimer’s disease: Aβ 1–42 aggregation process. The results obtained show that model membranes containing DHA can solubilize and delay the aggregation processes of different amyloidogenic peptides, suggesting that a common mechanism of action should exist.

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