Author ORCID Identifier

https://orcid.org/0000-0002-1839-0540

Semester

Spring

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

Zachary Weil

Committee Co-Chair

Candice Brown

Committee Member

Candice Brown

Committee Member

Ekaterina Weil

Committee Member

Paul Chantler

Committee Member

Courtney DeVries

Abstract

Ischemic stroke is the leading cause of long-term disability world-wide. These disabilities can include both cognitive impairment and sensorimotor deficits. Due to the prevalence of post-stroke functional deficits, it is imperative to identify novel therapeutic targets and develop new treatments. These cognitive deficits are a result of damage to the neurovascular unit (NVU), a term used to describe the relationship between the cerebral vasculature and other cell types within the brain. Cognitive impairment as a result of damage to the NVU is referred to as vascular contributions to cognitive impairment and dementia (VCID), and it is estimated that between 25-30% of ischemic stroke survivors will develop some degree of VCID. While VCID can develop quickly following a stroke, some patients experience the onset several years after the initial stroke. Neuropathology, such as neuroinflammation, cerebral microhemorrhages, microinfarcts, cerebral edema, and white matter damage, can be utilized to determine the level of risk of developing VCID. While the primary risk factor of developing VCID is an ischemic stroke, other risk factors such as cardiovascular dysfunction, age, and biological sex can increase the risk of developing VCID post-stroke.

In chapter 2, I investigated how pre-existing neurological disease (Alzheimer’s disease [AD]) can impact post- stroke neuropathology leading to VCID. In this study, I found an increase in AD-like pathology post-stroke in addition to increased neuropathology known to lead to VCID, such as microhemorrhaging, cerebral edema, and white matter damage. This shows that the presence of AD-like pathology leads to an increased risk of developing VCID post-stroke.

In chapter 3, I investigated the potential role of endothelial cell (EC) tissue-nonspecific alkaline phosphatase (TNAP) in maintaining the NVU post-stroke. In this study, I found that the loss of EC TNAP resulted in an increased risk of developing neuropathology leading to VCID, such as increased neuroinflammation, cerebral edema, microhemorrhaging, and white matter damage. This shows that the loss of EC TNAP can result in an increased risk of developing VCID post-stroke.

In chapter 4, I investigated advanced age as a factor for developing VCID. In this study, I found that with advanced age, there is less of an effect of EC TNAP in the preservation of the NVU, likely due to age-related confounds. This emphasizes the need for stroke studies to occur in an aged population, as this is the population most vulnerable to strokes.

Throughout chapters 2, 3, and 4, I investigated the impact of biological sex on the occurrence of VCID post-stroke. Sex-differences are well-documented in ischemic stroke; however, most stroke studies are conducted on males, resulting in a large knowledge gap on the differences that occur in males and females post-stroke. For this reason, all experiments are conducted in both males and females, and all sex differences are reported.

Lastly, I utilized extracellular vesicle (EV) profiling and metabolomics to identify a potential mechanism of action as to why EC TNAP influences post-stroke VCID. I have shown here that the loss of EC TNAP results in altered EV signaling, this altered signaling resulted in impaired EC function. By characterizing circulating EVs, we are able to identify a novel biomarker for the risk of VCID post-stroke.

The data in this dissertation serves to provide novel insight into the rapidly expanding field of ischemic stroke, VCID, and EVs. The work conducted emphasizes risk factors for developing VCID post-stroke, identifies a novel role for TNAP in the preservation of the NVU, and links potential mechanisms of action for the role of EC TNAP in the NVU.

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