The Amyloid-β peptide (Aβ-42) can be expressed through cleavage of a precursor protein (APP) during post-translational modification as a result of oxidative stress in the brain. Once expressed, the peptide will readily form binding interactions with free metal ions, particularly Cu2+, initiating a series of redox reactions that result in the production of Reactive Oxygen Species (ROS) and amyloid plaques within the brain. This process has been implicated as the major contributing factor in neurodegeneration in Alzheimer’s patients. Recent investigations from the literature have shown that two major Aβ-Cu complexes are formed at the Aβ-42 active site upon coordination, and one of these complexes readily reduces Cu2+ to Cu+ generating ROS via Fenton Decomposition. An increasingly promising area of study in the treatment of AD is to disrupt this pathway using metal ion chelation, which can serve as a form of therapeutic treatment. The work presented herein focuses on different copper coordination compounds and their redox activity using various ligands such as glycine, beta alanine, phenylalanine, 2,2’-bipyridine (bipy), 2,2’-thiodipyridine (DPS), 2,2’-dipyridylamine (DPA), and 1,10-phenanthroline-2-thiopyridine (TPP). Utilizing Cyclic Voltammetry to monitor redox activity, the more stable ligand complexes resulted in a more quasi-reversible cyclic voltammogram, allowing for potential redox cycling between Cu2+ and Cu+ at the Aβ-42 active site. The CV results correlated well with hydroxyl radical trapping experiments that measured the rate of hydroxyl radical production in each complex, and a relationship between redox activity and hydroxyl radical production was observed. These results provide valuable insight into ligand design characteristics important for the development of potential therapeutic treatments that slow AD progression.

Comparison of Cu-ligand complexes for Aβ-42 therapeutic chelating agents

2019 Spring National Meeting

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