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

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Alzheimer’s disease
Multifunctional ligands
Metal binding

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).

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This thesis may be printed or downloaded for non-commercial research and scholarly purposes. Copyright remains with the author.
Tim Storr
Thesis type: 
(Thesis) Ph.D.