Dissertations, Theses, and Capstone Projects

Date of Degree

9-2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Biology

Advisor

Peter Serrano

Committee Members

Maria Figueiredo-Pereira

Alejandra Alonso

Pinar Ayata

Tristan Shuman

Subject Categories

Biology | Molecular and Cellular Neuroscience

Abstract

Alzheimer’s disease (AD) is a debilitating neurological condition ranked as the fifth leading cause of death in adults over the age of 65. Despite the severity, 98% of drugs have failed as treatments for AD. Current novel drug development approaches have been unable to produce a disease-modifying treatment as they often have a one-target approach, not accounting for the complex nature of the disease. One of the hallmarks of the disease, inflammation, may provide a better target for treatment because it interacts with multiple facets of the disease. Drug repurposing to identify compounds that mitigate inflammation in AD could provide a fast and effective treatment. This analysis has suggested Atractylenolide III (ATC-III) as a candidate for an AD drug treatment because of its strong implications in multiple inflammatory pathways. The GOAL of my studies was to examine the potential therapeutic effects of ATC-III and its mechanism of action in an AD model. My hypothesis was the ATC-III would ameliorate cognitive and molecular AD pathology through its anti-inflammatory effects. The rationale for my hypothesis is that ATC-III improved inflammation, neurodegeneration, and cognitive deficits in multiple models of neuronal damage acting primarily through the NF-κB or Jak2/STAT3 pathways.

The results of my studies are reported in the following chapters:

Chapter 2: ATC-III improves spatial cognitive performance in male TgF344-AD rats I found that long term treatment of ATC-III rescued spatial learning deficits in aged TgF344-AD male rats but not spatial memory and did not affect cognition in wildtype or TgF344-AD female rats.

Chapter 3: ATC-III differentially affects hallmark AD pathology across sex and genotype My studies examining the effect of ATC-III on molecular AD pathology reveal that ATC-III increased counts of activated microglia in male TgF344-AD rats and decreased activated microglia in female TgF344-AD rats and male and female wildtype rats. Additionally, both hyperphosphorylated tau and neuronal loss were exacerbated with ATC-III treatment.

Chapter 4: ATC-III causes sex-dependent transcriptional changes in TgF344-AD model Analysis of the transcriptional effects of ATC-III show that it causes distinct sex-specific changes in TgF344-AD transcriptomes. Further analysis of differentially expressed genes reveal that both the changes in male and female TG rats are involved in the NF-κB and JAK2/STAT3 pathways.

Conclusions: My data supports that ATC-III could be a potential therapeutic for AD. The sex- and genotype- dependent changes in pathology provide insight to understanding the environment specific mechanism of action for ATC-III. My study significantly contributes to understanding the role of inflammation and anti-inflammatory therapeutics for AD

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