Date of Award

Summer 2025

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Fiona Hollis

Second Advisor

Camilla Wenceslau

Abstract

Alzheimer’s disease (AD) is the most common form of dementia with 6.9 million Americans aged 65 years and older living with AD in 2024. Furthermore, cardiovascular diseases (CVDs) and cardiovascular risk factors are associated with an increased risk of AD and mild cognitive impairment, and the interaction between vascular and neurodegenerative processes has been proposed to be synergistic and to occur early in disease pathogenesis. However, the precise mechanisms and molecular processes that are likely associated with the incidence of these two leading aging-related chronic diseases remain elusive. To this end, the research question of our study was whether peripheral vascular dysfunction plays a critical role in the development of AD pathology, and this informed the overarching hypothesis of our study, that healthy vascular endothelial cells sense the presence of SPOs leading to vascular dysfunction, and systemic vascular dysfunction occurs prior to the development of amyloid pathology in early onset Alzheimer’s disease (EOAD).

To address these questions, we first hypothesized that SPOs can be recognized by the peripheral vasculature leading to ER stress and vascular injury. We showed that acute application of SPOs causes pathologically exacerbated endothelium-dependent vasodilation via generation of nitric oxide. In addition, SPO-induced ER stress in the endothelial cells increased mitochondrial reactive oxygen species (ROS) and loss of locomotor filaments but was able to maintain cell viability, indicating that short-term treatment of endothelial cells with SPOs does not lead to cell death, but it causes vascular dysfunction.

On the second part of our study, we investigated whether peripheral vascular dysfunction would precede amyloid pathology. Although there is evidence that amyloid deposition in the vessels can cause structural or cellular changes in arteries of patients with CVD and pause as a risk factor for cognitive decline later in life, it remains unknown whether systemic vascular dysfunction occurs prior to the development of AD, whether this occurs in a sex-dependent manner, or whether vascular tissue could play a role in the deposition of Aβ peptides. This was our hypothesis, and to test it, we used a mouse model of EOAD (APP/PS1), to evaluate vascular function in peripheral arteries prior to (3 months old) and during (7 months old) the onset of amyloid pathology. Our findings showed that endothelial dysfunction occurs prior to the onset of amyloid pathology independent of sex. This was evidenced by the resistance arteries showing impaired relaxation to acetylcholine (ACh) which is a muscarinic receptor agonist that causes endothelium-dependent vasodilation. These novel findings play a crucial role in highlighting that although the APP/PS1 mice are genetically modified to have increased amyloid deposition, peripheral vascular dysfunction occurs prior to the increased deposition of A in EOAD, and this can affect the autoregulation of blood vessels and in the long-run, interfere with cerebral blood flow in the brain. In addition, we observed that during the onset of amyloid pathology, the female APP/PS1 mice had increased deposition of A1-42 peptides which colocalized with endothelial cells in the blood vessels of the hippocampus. Furthermore, the female APP/PS1 mice had increased arterial stiffness. This interesting finding led us to question whether the increased arterial stiffness could lead to increased pulsatile pressure which can in turn trigger the endothelial cells in the cerebral microvessels to release more Aβ peptides, thus impairing cerebral vascular function. Although we did not assess this phenomenon in the course of this project, future studies are proposed to demystify these observations.

Finally, the last part of our study investigated the peripheral vascular remodeling and maladaptation that occurs during chronic amyloid pathology in 22- month-old male and female APP/PS1 mice. It is shown that the development of peripheral vascular dysfunction, characterized by large elastic artery stiffening and endothelial dysfunction with aging contributes to cardiovascular complications that compound the neurodegenerative processes in the central nervous system, further accelerating the progression of AD. Therefore, we hypothesized that peripheral arteries would present with endothelial dysfunction, increased collagen deposition hence increased pulse wave velocity, and increased Aβ1-42 deposition resulting in impaired blood flow regulation. Our findings showed that the resistance arteries from the aged male and female APP/PS1 mice had impaired endotheliumdependent relaxation, and they had increased collagen deposition in the aortas. Although there could be trans-gene effects of the animal model, the gene expression levels of the amyloid precursor protein (APP) in the aortas were not increased indicating that the observed peripheral vascular dysfunction could be driven by the aging process in these mice. However, further studies are needed to distinguish whether these effects are due to aging or due to the amyloid pathology. Overall, the findings from our study show that Aβ1-42 propagates its toxic effects in the peripheral vasculature by triggering molecular events that could progressively become detrimental in aggravating peripheral vascular function during the development of amyloid pathology. Further, we highlight the link between AD and CVD, by demonstrating that peripheral vascular abnormalities may be an early marker and potential mediator of early onset Alzheimer’s disease (EOAD). This could inform novel therapeutic strategies that target vascular health, offering a new approach to prevent or delay the onset of Alzheimer's disease and other neurodegenerative diseases.

Rights

© 2025, Emily Wanjiku Waigi

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Available for download on Tuesday, August 31, 2027

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