Date of Graduation


Document Type


Degree Type



School of Medicine


Not Listed

Committee Chair

James Simpkins

Committee Member

Candice Brown

Committee Member

Lisa Salati

Committee Member

Paul Lockman

Committee Member

Werner Geldenhuys

Committee Member

Elizabeth Engler-Chiurazzi


Alzheimer’s disease (AD) is a terminal illness and the most common form of dementia, which disproportionately affects the aged population. The pathophysiology of AD is characterized by neurodegeneration that slowly progresses, affecting regions of the brain that are involved in learning, memory, language, and executive function. In patients with the disease, early symptoms include non-disruptive forgetfulness that evolves into the inability to form new memories and ultimately the loss of autonomy at late stages. Histopathological hallmarks in the brain from patients with AD is the presence of amyloid-β (Aβ)-plaques and neurofibrillary tangles (NFT) deposited in the parenchyma. Since the discovery of these hallmarks, the majority of AD research has disproportionately focused on Aβ -plaques and NFT. Although the etiology of AD remains unknown, considerable advances have been made describing the cellular, molecular, and genetic contributions to the disease. Aging is the important risk factor for the development of AD, many other factors that increase the risk of developing AD later in life are vascular in nature. The function of the cardiovascular system is known to decline during healthy aging, and the same is true for the cerebrovasculature. Empirical evidence has demonstrated a decline cerebrovascular function in AD that exceeds the decline that occurs in healthy aging. Cerebrovascular dysfunction is the major contributor to the development of hypoperfusion and hypometabolism in patients diagnosed with AD. Cerebral amyloid angiopathy (CAA) is a neuropathological condition defined by the abnormal accumulation of Aβ on the walls of the cerebrovasculature. CAA occurs in as many as 90% of patients with AD and is implicated in the weakening of the walls of cerebral blood vessels. The occurrence of microhemorrhages, aneurysms, and microinfarctions are pathological manifestations associated with weakened walls of cerebral blood vessels in the brains of patients with confirmed AD. Noteworthy, cerebrovascular dysfunction, hypoperfusion, and hypometabolism occur before the onset of Aβ-plaque and NFT deposition in the brain of patients and animal models with AD. These findings provide a compelling basis that suggest a prominent role of dysfunctional cerebrovasculature in the etiology and for the progression of AD.

Although the overwhelming evidence that implicates cerebrovascular dysfunction in AD, a thorough account of the changes that occur to the cerebrovasculature nor the mechanisms that drive these changes during the development and progression of AD has not been previously reported. The overarching goal(s) of this work are to; (1) provide a thorough description of the changes that occur to the cerebrovasculature during age and the progression of AD; (2) describe the mechanisms involved in cerebrovascular damage in AD; and (3) characterize the degeneration that results from cerebrovascular hypoperfusion. These overarching goals were achieved by completing five separate studies. Described in study 1, we investigated the effects of hypoxia on astrocytic mitochondria by assessing mitochondrial fission-fusion dynamics, reactive oxygen species production, synthesis of ATP, and mitophagy. Overall, we found a drastic mitochondrial network change that is triggered by metabolic crisis during hypoxia; these changes are followed by mitochondrial degradation and retraction of astrocytic extensions during reoxygenation. In study 2, we provide a novel model for the gradual development of cerebrovascular hypoperfusion in mice. Cerebrovascular hypoperfusion developed over 34-days by inserting an ameroid constrictor ring and microcoil bilaterally around the external carotid arteries. We investigated the neurodegenerative effects of hypoperfusion in mice by assessing both gray and white matter pathology. Histopathological analyses of the brain revealed neuronal and axonal degeneration as well as necrotic lesions. The most severely affected regions were located in the hippocampus and corpus callosum. Described in study 3, we performed a series of experiments to investigate the effects of Aβ on cerebrovascular endothelial cells. In this study, we focused on characterizing the changes to mitochondrial oxidative phosphorylation, superoxide production, mitochondrial calcium, ATP synthesis, and endothelial cell death. These results describe a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which was driven by increased mitochondrial Ca2+ uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. In study 4, we developed a method to evaluate the cerebrovasculature of the whole-brain and constructed analyses to assess the angioarchitecture. We used vascular corrosion casting method to replicate the cerebrovasculature in adult mice and used MicroCT to acquire volumetric imaging data of the cerebrovascular network at a resolution required to investigate the microvasculature. Our analyses of the cerebrovasculature evaluated the morphology, topology, and organization of the angioarchitecture. With these developments, we investigated the effects of age and progression of disease on the cerebrovasculature in wild type mice and the triple transgenic mouse model of AD. Study 5 provides data describing degenerative changes to the microvascular network that progress with age in the triple transgenic mouse model of AD. These changes to the microvasculature occurred early, before the onset of Aβ-plaque deposition and NFT development.

Overall, this body of work provides evidence of an early cerebrovascular disruption in the etiology of AD that progresses with age. Aβ mediates early cerebrovascular damage through direct interaction with vascular endothelial cells. Microvascular degeneration can lead to hypoperfusion which damages both gray and white matter. Hypoperfusion-associated hypoxia may mediate parenchymal damage by disrupting mitochondrial fission-fusion dynamics and enhancing mitophagy. These data provide a basis for the development of novel therapeutic strategies that target the changes to the cerebrovasculature for the treatment of AD. These observations may substantiate a prophylactic strategy for the treatment of AD by preventing the initial factors that lead to compromised cerebrovasculature.