Small molecule agents that target amyloid-β aggregation in Alzheimer's disease

Alzheimer’s disease (AD) is the most common form of dementia and currently there is no cure. AD is characterized by the formation of two pathological hallmarks; aggregated forms of the amyloid-β (Aβ) peptide called Aβ plaques and hyperphosphorylated tau proteins, called neurofibrillary tangles (NFT). Aβ is enzymatically cleaved from the amyloid precursor protein (APP) to afford a 38-43 amino acid residue peptide with Aβ1-40 and Aβ1-42 being the most common. Plaque deposits have been shown to contain abnormally high concentrations of dysregulated metal ions, specifically Cu, Zn, and Fe. Metal-Aβ interactions have been shown to increase the rate of Aβ aggregation leading to increased neurotoxicity and oxidative stress. Specifically, Cu-Aβ species in stoichiometric amounts produce soluble, oligomeric species, which are hypothesized to play a role in AD. This thesis presents several strategies to influence metal-Aβ interactions in order to mitigate peptide aggregation and overall toxicity. Three triazole-based ligand scaffolds are presented that were designed to exhibit a range of properties including metal binding, peptide interactions, and antioxidant capabilities. Chapter 2 describes a series of pyridine-triazole ligands that have an affinity for the N-terminus region of the Aβ peptide where metal binding occurs. Chapter 3 builds from the previous chapter by extending the aromatic ring system to present a series of quinoline-triazole ligands. This framework demonstrated interactions with the peptide in the hydrophobic region (residues 17-21) of the peptide and was able to influence Cu-Aβ aggregation. Finally, chapter 4 describes a series of phenol-triazoles that compete with Aβ for binding of free Cu, interact in the hydrophobic region of the Aβ peptide, and exhibit antioxidant properties. Chapter 5 presents a new strategy to prevent Aβ aggregation through the use of KP1019, a Ru(III) anticancer agent. KP1019 readily binds to the Aβ peptide within 2 hours, modulating Aβ aggregation by producing non-toxic aggregates as demonstrated in a human neuroblastoma cell line (SH-SY5Y).