Date of Award

5-24-2019

Document Type

Thesis

Degree Name

Bachelor of Science (B.S.) in Health Studies: Health Sciences and University Honors

Department

Health Studies

First Advisor

Marilyn Mackiewicz

Subjects

Alzheimer's disease -- Pathogenesis, Amyloid beta-protein, Active oxygen -- Toxicology, Nervous system -- Degeneration, Ligands

DOI

10.15760/honors.814

Abstract

Alzheimer’s Disease (AD) is the sixth leading cause of death in the United States with no known methods to cure, reverse or halt disease progression. The “metal hypothesis” states that CuII, FeIII, ZnII and AlII bind to truncated beta amyloid (Aβ) peptides and form soluble oligomers which deposit as senile plaques. These plaques play a crucial role in AD pathogenesis. For example, metallated-Aβ aggregates are hypothesized to disrupt membranes or generate a reactive oxygen species (ROS) through redox cycling in the presence of CuI/ll or FeIII/ll and a reducing agent. ROS can lead to weakened synaptic signaling and neuronal cell death. In addition, the ratio of the metal:Aβ can form a variety of metallated-Aβ species which are both soluble and neurotoxic. Neurotoxicity can depend on the size of the metallated-Aβ species as well as the type of metal present. For example, some studies suggest that CuII ions inhibit aggregation and fibrillation reactions induced by ZnII ions and may therefore be neuroprotective in this scenario. Regardless to the contradicting roles of metals, the most convincing piece of evidence supporting a link between metal homeostasis and the two pathological processes (Aβ1-42 aggregation and oxidative damage) comes from chelation studies showing solubilization of Aβ1-42 deposits and clinical improvement of patients with AD. Studies suggest control of metal imbalances as well as Aβ1-42 concentrations are important “disease-modifying strategies”. Here we will present studies utilizing well-known metal ion capture agents, metallodithiolates or NiN2S2 ligands, as chelators to reverse Aβ1-42 aggregation. Fluorescence anisotropy, UV-Vis spectroscopy, and atomic force microscopy studies will show that interactions of Aβ with metal ions are reversible with metallodithiolate ligands. These studies will show that metallodithiolates might be a new class of ligands for reversing metal-induced Aβ aggregation and a potential disease modifying strategy.

Persistent Identifier

https://archives.pdx.edu/ds/psu/30545

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