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Date of Award

Spring 5-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Chemistry

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disease, currently affecting 5 million in the US and 25 million population worldwide. Unfortunately, there is no treatment for AD, and its accurate diagnosis requires a detailed post-mortem examination of the brain. The formation of extracellular amyloid plaques containing the amyloid β (Aβ) peptide is one of the pathological hallmarks in the brains of Alzheimer’s patients. In addition, numerous studies show that the metal ions can interact with the Aβ peptides and affect the aggregation process dramatically, especially for copper ions that can stabilize the Aβ oligomers, leading to high neurotoxicity.

In this regard, we developed a series of novel bifunctional molecules that have high binding affinity with various Aβ42 species and strong metal-binding ligands to modulate the interaction of copper ions with Aβ42 species to alleviate the Cu2+-induced Aβ42 cytotoxicity. Different Aβ binding fragments, bis-styryl stilbene and benzofuran derivatives, were synthesized successfully and modified by adding strong metal-binding ligand through the Mannich reaction. Several in vitro assays were performed to evaluate the ability to quench ROS and attenuate the cytotoxicity of Cu2+-induced Aβ species. Moreover, immunostaining studies were also employed to see the binding specificity of the compounds. The fluorescence images show that most of the bifunctional compounds can bind to the amyloid plaques specifically. More interestingly, some of the compounds show high binding specificity of soluble Aβ oligomers, confirming by the oligomer-specific antibody labeling.

Furthermore, the novel bifunctional compounds were also evaluated as PET imaging agents for AD. Taking advantage of the high binding affinity with Cu2+, the developed bifunctional compounds were preloaded with 64Cu, and these 64Cu complexes were evaluated to be potential PET imaging agents for Alzheimer’s Disease. According to the in vitro results, several compounds were selected for biodistribution studies to characterize further the imaging properties in vivo. Overall, these studies lend promise to our future studies aimed at developing improved bifunctional compounds as novel theranostic agents, given the dearth of treatment and diagnostic tools for AD.

Language

English (en)

Chair and Committee

Liviu M. Mirica Michael Gross

Committee Members

Meredith Jackrel, Buck E. Rogers, John-Stephen Taylor,

Comments

Permanent URL: https://doi.org/10.7936/rfgv-2t72

Available for download on Monday, May 15, 2119

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