Date of Award


Degree Type


Degree Name

Doctor of Philosophy in Interdisciplinary Neuroscience


Interdisciplinary Neuroscience

First Advisor

Paula Grammas


Alzheimer’s disease (AD) is the most common form of dementia, affecting 5.8 million people in the United States alone. Currently, there are no disease-modifying treatments for AD, and the cause of the disease is unclear. With the increasing number of cases and the lack of treatment options, AD is a growing public health crisis. As such, there is a push for investigation of novel pathological mediators to inform new therapeutic approaches.

Cardiovascular disease and associated cardiovascular risk factors (CVRFs) are linked to a significantly increased risk for developing AD, but the mechanisms whereby these risk factors contribute to the pathological processes in the AD brain have not been defined. Because CVRFs affect vascular function, a dysfunctional cerebrovasculature could be an important driver of CVRF-induced injury in the AD brain. Furthermore, the cerebrovasculature is both a source of, and target for, inflammatory mediators, indicating that a dysfunctional cerebrovasculature likely participates in the robust neuroinflammatory response found in the AD brain.

In particular, type II diabetes mellitus (T2D) is associated with a more than doubled risk for developing AD. Hyperglycemia-induced endothelial activation and related inflammatory processes are key pathological features in T2D. Here, we investigate vascular dysfunction and neuroinflammation in diabetes-like conditions in vitro. Results show that brain endothelial cells treated with hyperglycemia and hypoxia in vitro become injured and release inflammatory mediators. This endothelial injury activates a pro-inflammatory microglia phenotype in a co-culture system, characterized by significantly increased production of inflammatory cytokines and nitric oxide (NO), and increased expression of microglia activation markers. These microglia changes mimic those found in the AD brain, highlighting that endothelial damage and dysfunction may be a driver of neuroinflammatory activation in AD.

Mutations to the lipid transport protein apolipoprotein E (ApoE) have been identified as the strongest genetic risk factor for sporadic or late-onset AD, with the E4 allele representing an increased risk and the rare E2 having a reduced risk compared to the primary E3 form. While the risk is well documented, the mechanisms responsible for this risk are not well understood. We examined the effects of ApoE isoforms on markers related to vascular function, neuroinflammation, and neurotoxicity using in vitro and in vivo models. In vitro, the ApoE4 isoform induces pro-inflammatory activation of both microglia and astrocytes, as well as enhanced neurotoxicity. On the other hand, ApoE2 promotes neuronal survival through both direct and indirect actions on neurons. Using an in vivo mouse model, we show that ApoE4 promotes blood-brain barrier dysfunction and neuroinflammation, characterized by loss of tight junction proteins, and increased oxidative stress and pro-inflammatory cytokines. Additionally, our results indicate that the ApoE4 isoform promotes an inflammatory-oxidative state to a greater extent in female mice than in males.

Recent research indicates that components of the coagulation cascade may act as mediators of vascular dysfunction and inflammation in both cardiovascular disease and in AD. One such protein is the serine protease thrombin, which is elevated in the AD brain. Here, we present an extensive literature review, which posits that thrombin acts on endothelial cells of the blood-brain barrier, microglia, astrocytes, and neurons in a manner that promotes vascular activation, inflammation, and neurodegeneration. Additional evidence suggests that pharmacologically targeting thrombin may be an effective treatment strategy for targeting multiple points of AD pathology. We investigated thrombin’s role as a pathological mediator and potential therapeutic target and show that treatment of a tau-based AD mouse model in vivo with the direct thrombin inhibitor dabigatran produced significantly reduced oxidative stress and tau phosphorylation, and promoted cell survival and synaptic function.

Taken together, our results suggest vascular activation and related neuroinflammation as possible convergence points whereby CVRFs promote AD-related pathological processes. Furthermore, we highlight shared pathological mediators that may represent novel therapeutic targets for the treatment of multiple points of pathology in AD.



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