Misfolding of proteins into amyloid structures is implicated as a pathological feature in several neurodegenerative diseases and the molecular causes are still unclear. One typical characteristic of Alzheimer’s disease is self-assembly and accumulation of soluble amyloid-β (Aβ) peptides into insoluble fibrils and plaques. One way to provide fundamental knowledge about the underlying fibrillization processes is to perturb the aggregation by varying the experimental conditions. Two main aspects are included in this thesis work: interactions with the Aβ peptide, and modulation of the Aβ peptide aggregation kinetics. The interplay between the Aβ peptide and three different types of aggregation modulators was studied mainly in vitro by biophysical techniques such as NMR, circular dichroism, and fluorescence spectroscopy.

Metal ions, such as Ag(I), Cu(II), Hg(II), and Zn(II), at sub-stoichiometric concentrations with specific binding to monomeric Aβ peptides modulate and attenuate the Aβ self-assembly process. The bound (metal:Aβ) state removes Aβ monomers from the monomeric pool of amyloid building blocks used for fibril formation. In contrast, designed peptide constructs with cell-penetrating properties do not interact with monomeric Aβ, but exhibit an inhibitory effect on the Aβ oligomerization and fibrillization in vitro and in cells, via interactions with multimeric Aβ structures. The designed peptide constructs rescue Aβ-induced neurotoxicity and target both intracellular and extracellular Aβ. Full-length and native Tau protein, another protein implicated in Alzheimer’s disease, prevents the Aβ peptide fibrillization. The Aβ fibrillization process is not prevented by Tau interactions with the Aβ monomeric species, but rather with fibrils and oligomeric species of Aβ.

Here we showed that the Aβ peptide interacts with various metal ions and molecules, both at the monomeric stage and as larger assemblies, with resulting perturbation of the Aβ aggregation kinetics. The interactions and aggregation modulators can be used to learn more about the underlying fibrillization processes and for the development of potential therapeutic strategies.