Date of Award

8-5-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Information Science

First Advisor

Steven Barger

Abstract

Alzheimer’s disease (AD) is an example of a neurodegenerative disease, mostly age related and characterized by cognitive decline. Currently there is no effective treatment that can prevent or slow progression of the disease. Roughly 95% of cases are sporadic, with unknown etiology. A distinguishing characteristic of the Alzheimer’s brain is the presence of amyloid plaques, with their constituent amyloid-β (Aβ) peptides implicated in causing synaptic dysfunction, memory impairment, and neurotoxicity. Although extensive research has explored the role of Aβ peptides in AD, understanding their metabolism in health versus disease remains insufficient. P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter superfamily, is a membrane protein with broad substrate specificity. Its expression and function in the brain decline with age, Aβ deposition, and AD progression. While P-gp has been identified as exporting Aβ peptides across the blood-brain barrier, the corresponding role, if any, in the egress of Aβ with or in the presence of other P-gp substrates remains largely unexplored, representing a significant knowledge gap. This work is centered on the exploration of the P-gp transporter and its role in exporting Aβ peptide and other P-gp substrates concerning AD. In Chapter 1, an overview of P-gp's involvement in the pathogenesis of AD is provided, along with a discussion of potential therapeutic interventions, including pharmacological modulators. Chapter 2 details a cohort study, utilizing data from the PharMetrics Plus database (IQVIA) to investigate P-glycoprotein substrate (Pgp-S) users and AD risk. The study population is examined through propensity score matching to balance demographic factors between Pgp-S users and non-users. Cox regression models, adjusted comorbidities, are employed to explore the association between Pgp-S use and the incidence of AD. Odds ratios for AD to Pgp-S use are also analyzed. Notably, individuals exposed to P-gp substrates generally exhibit a lower probability of converting to an AD diagnosis compared to non-users. However, it's crucial to highlight that this protective effect is reversed in the presence of certain comorbidities, leading to an apparent enhanced risk. Chapter 3 focuses on optimizing the cell permeability assay system for increased efficiency, reliability, and reproducibility. Variables considered include cell selection, factors influencing cell integrity, and protocol optimization for the transport of fluorescently labeled Aβ peptides and other FDA-approved drugs that are P-gp substrates selected from Chapter 2. The presence of substrates with lower odds appear to enhance the efflux of Aβ. The goal was to determine the efflux of Aβ in the presence and absence of Pgp-S. In Chapter 4, the molecular interaction between Aβ and P-gp in with the introduction of other P-gp substrates (drugs, used in Chapter 3) are investigated through molecular modeling and simulations. The analysis reveals a favorable interaction of Aβ to P-gp in the presence of substrates that had lower odds of incidence of AD in Chapter 2 and less favorable with the one with a higher odds ratio. In conclusion, the findings presented in this dissertation offer insights into how certain FDA-approved drugs may influence the risk of AD. The study also reinforces the role of P-gp in the transport of substrates, including Aβ. This exploration contributes valuable insights into the intricate interplay between Pgp-S use and AD risk, suggesting potential directions for future research and therapeutic approaches.

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