Evaluation of small molecules and metal complexes that modulate amyloid-beta aggregation of relevance to Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia, representing 50-75% of all cases worldwide. AD is a multifaceted disease that is characterized by increased oxidative stress, metal-ion dysregulation, and the formation of intracellular neurofibrillary tangles and extracellular amyloid-B (AB) aggregates. Cu(II), Zn(II) and Fe(II) have been shown to play a role in the aggregation and toxicity of the AB peptide, leading to the formation of reactive oxygen species (ROS) for Cu(II) and Fe(II). Different approaches have been used in this thesis to decrease the formation of ROS, modulate peptide aggregation and the interaction between bioavailable metal ions and the AB peptide. In the first approach, metal-protein attenuating compounds (MPACs) were designed to bind dysregulated metal ions thereby limiting metal ion binding to the AB peptide. The ability of 8-hydroxyquinoline Schiff-base ligands to inhibit peptide aggregation in the presence of Cu(II), and their antioxidant activity measured by a Trolox equivalent antioxidant capacity (TEAC) assay are described. The ligands were shown to form complexes with Cu(II), 8-H2QT in a 1:1 metal:ligand ratio, and 8-H2QH and 8-H2QS in a 1:2 metal:ligand ratio. The second approach investigated herein describes the use of metal complexes that are able to bind to the peptide, with potential to modulate aggregation and limit ROS formation. We report the high affinity binding of the Fe(III) 2,17-bis-sulfonato-5,10,15-tris(pentafluorophenyl)corrole complex FeL1 to the AB peptide (Kd ~ 10-7) and the ability of the bound FeL1 to act as a catalytic antioxidant in both the presence and absence of Cu(II) ions. Overall, FeL1 is shown to bind to the AB peptide, and modulate peptide aggregation. In addition, FeL1 forms a ternary species with AB-Cu(II) and impedes ROS generation. Finally, we report a series of four Ru(III) complexes, inspired by the antimetastatic NAMI-A complex. These complexes bind to AB, and were shown to modulate peptide aggregation. Overall, we highlight the promise of discrete metal complexes to limit the toxicity pathways of the AB peptide.