Date of Award

2016

Document Type

Open Access Dissertation

Department

Biomedical Engineering

Sub-Department

College of Engineering and Computing

First Advisor

Melissa A. Moss

Abstract

Alzheimer’s disease (AD) is a neurodegenerative condition that affects 1 in 9 people over the age of 65, an estimated 5.4 million Americans. It is the only disease among the top 10 that cannot be prevented, cured, or treated. Based on the lack of a viable therapeutic for the prevention or cure of AD, it is vital that therapeutic research for AD continues. AD is characterized by the deposition of extracellular neuritic plaques comprised of insoluble amyloid-β (Aβ) fibrils. These plaques are formed from the amyloidogenic aggregation of Aβ monomer, generated from the cleavage of the amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. Aβ monomer aggregates via a nucleation-dependent pathway to form insoluble Aβ fibrils (fAβ). Many Aβ aggregates formed along the nucleation-dependent pathway are neurotoxins, associated with cognitive decline and neuronal loss observed in AD patients. Thus, one therapeutic strategy is to target the production of Aβ and/or its subsequent aggregation.

Epidemiological studies have associated green tea, rich in catechin polyphenols, and black tea, rich in theaflavin polyphenols, with reduced incidence of AD. The present study sought to explain this correlation, by identifying their potential to act as multi-target therapeutic drugs for AD by 1) altering the mechanistic aggregation of Aβ and 2) altering Aβ1-42 oligomer-induced expression of key AD-associated mRNAs.

Catechins and theaflavins showed mechanistic inhibition towards Aβ aggregation. Catechins inhibit only the late stages of Aβ soluble aggregate growth, suggesting the ability to bind only large Aβ aggregate conformations. Theaflavins displayed a more sweeping capability, showing slight to prominent inhibition across the mechanistic steps of Aβ aggregation. Both catechins and theaflavins were able to alter the morphology of fAβ made in their presence. fAβ structural conformation, or morphology, has been correlated with cytotoxic effects.

While theaflavins showed promising capabilities to inhibit the overall mechanistic aggregation of Aβ, catechins displayed higher capabilities to alter Aβ-oligomer induced expression of key AD-associated mRNAs. Epigallocatechin (EGC) and epigallocatechin gallate (EGCG) through antioxidant and antiaggregation capabilities, respectively, were able to attenuate the oligomer induced upregulation of APP, thus potentially reducing the APP protein that can be cleaved to release A. Additionally, through antiaggregation capabilities EGC and EGCG were able to significantly increase RNA expression of ADAM10, which cleaves APP in a manner that prevents A release. All catechins were able to attenuate Aβ-induced expression of BACE1 mRNA through antiaggregation capabilities. In combination, these studies identify the capabilities of catechins to alter the pre-processing and post-processing of Aβ, supporting their potential to act as multi-target therapeutics.

Rights

© 2016, Shelby Elaine Chastain

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