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THE ROLE OF AGGREGATED TAU ON ENDOTHELIAL AND CEREBROVASCULAR DYSFUNCTION
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Thesis/Dissertation
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2025-05
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Biomedical Sciences
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https://doi.org/10.34944/0ht0-2d92
Abstract
The presence of tau in the brain vasculature is a prominent feature of tauopathies and neurodegenerative disorders, such as Alzheimer’s Disease, chronic traumatic encephalopathy and traumatic brain injury. Physiologically, microtubule associated protein tau regulates microtubule dynamics and stability in healthy neurons through a tightly regulated phosphorylation balance; however, in pathological states, tau becomes hyperphosphorylated, leading to its dissociation from microtubules and insoluble aggregation inside neurons. These oligomeric and fibrillar aggregated species of tau can move through the brain, through a process known as tau spreading; ultimately reaching the vasculature, likely for clearance purposes. Upon reaching cerebral blood vessels, these aggregates can elicit dysfunction of endothelial cells that line the inside of these vessels and are the site of the blood-brain barrier. These pathological events carry larger repercussions, affecting cerebral blood flow and proper brain function. Although there is a growing interest in the effects of tau on brain endothelial cells, the molecular mechanisms by which tau aggregates elicit endothelial dysfunction remain vastly understudied. Using human cerebral microvascular endothelial cells and the P301S model of tauopathy, this research sought out to understand how aggregated tau mediates endothelial stress responses: including endothelial bioenergetic alterations, endothelial cell pro-inflammatory activation, the unfolded stress response and receptor-mediated tau entry and signaling; that ultimately coalesce in loss of barrier resistance. These results indicate that aggregated tau fibrils cause an increase in glycolysis, tied to the upregulation of pro-inflammatory adhesion molecules (VCAM-1 and ICAM-1), cytokine production and release, and the disruption of tight junction expression and localization; all mediating the loss of endothelial barrier resistance in our in vitro model. These findings were recapitulated in the extracted vessels of our in vivo model, where altered glycolytic metabolism tight junction protein dysfunction and pro-inflammatory markers were found. Further, an increase in cerebral blood flow was observed at an early timepoint, where increased neurovascular coupling is possibly observed as a result of overactive neuronal firing due to the presence of tau in PS19 mice. Finally, we have shown that tau can enter endothelial cells through the receptor for advanced glycation end products, mediating an increase in glycolysis and thereby, the production of methylglyoxal, a reactive metabolite. Both methylglyoxal and tau can activate pro-inflammatory signaling and endoplasmic reticulum stress, the latter leading to the activation of unfolded protein response (mainly through the ATF6 branch). These pathways can ultimately promote a loss of barrier resistance and endothelial dysfunction. Overall, the results discussed in this thesis provide an understanding on the molecular mechanisms involved in endothelial dysfunction and provide novel targets for the development of therapeutic targets in the prevention and treatment of tauopathies.
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