Author ORCID Identifier
Semester
Spring
Date of Graduation
2026
Document Type
Dissertation (Campus Access)
Degree Type
PhD
College
School of Pharmacy
Department
Pharmaceutical Sciences
Committee Chair
Paul Chantler
Committee Member
Edwin Wan
Committee Member
Lori Hazlehurst
Committee Member
Werner Geldenhuys
Committee Member
Candice Brown
Abstract
Chronic psychological stress is a major mid-life risk factor associated with vascular dysfunction and an increased risk of cognitive decline and dementia. The brain relies on tightly regulated cerebral blood flow to meet metabolic demands, making cerebrovascular integrity essential for normal neural function. Cerebrovascular dysfunction is increasingly recognized as an early feature of Alzheimer’s disease (AD), preceding overt cognitive impairment and contributing to disease progression. Although chronic stress is known to impair vascular function and promote oxidative stress, the mechanisms linking stress exposure to sustained cerebrovascular dysfunction and accelerated AD pathology remain unclear. Xanthine oxidoreductase (XOR), a key enzymatic source of reactive oxygen species, represents a potential mechanistic link between stress-induced oxidative stress and neurovascular dysfunction. In this dissertation, I investigated the role of chronic stress in driving cerebrovascular dysfunction and accelerating AD progression, with a focus on XOR and associated redox–inflammatory pathways. Using male and female wild-type (WT) and triple-transgenic AD (3xTg-AD) mice, chronic stress was modeled via unpredictable chronic mild stress (UCMS) during mid-life, with or without pharmacological inhibition of XOR using febuxostat. Cerebrovascular function was assessed through ex vivo endothelial-dependent dilation of the middle cerebral artery, while global and regional cerebral blood flow (CBF) were measured using laser speckle contrast imaging. Behavioral outcomes were evaluated using open field, Y-maze, and novel object recognition paradigms, alongside molecular assessments of oxidative stress, XOR expression, and redox–inflammatory signaling. Chronic stress induced early cerebrovascular dysfunction marked by impaired endothelial function and reduced nitric oxide bioavailability in both WT and 3xTg-AD mice. These deficits were associated with increased oxidative stress and elevated XOR expression, supporting a central role for XOR-derived reactive oxygen species in mediating neurovascular dysfunction. Pharmacological inhibition of XOR restored endothelial function and improved cerebral perfusion. At the molecular level, stress-induced XOR activation disrupted redox homeostasis, characterized by impaired NRF2-mediated antioxidant signaling and enhanced NF-κB–driven inflammatory pathways, promoting a pro-oxidative and pro-inflammatory environment that contributes to sustained vascular dysfunction and AD-related pathology. Overall, this work identifies XOR as a critical mediator linking chronic stress to cerebrovascular dysfunction and AD progression through modulation of redox–inflammatory pathways. These findings provide a mechanistic framework connecting oxidative stress, vascular dysfunction, and neurodegeneration, and highlight XOR as a potential therapeutic target for mitigating AD progression.
Recommended Citation
Prabhu, Saina Sanjay, "Role of Xanthine Oxidase and Chronic Stress in Alzheimer's Disease Progression" (2026). Graduate Theses, Dissertations, and Problem Reports. 13337.
https://researchrepository.wvu.edu/etd/13337