Date of Award
Summer 7-21-2025
Embargo Period
8-6-2027
Document Type
Dissertation - MUSC Only
Degree Name
Doctor of Philosophy (PhD)
Department
Molecular and Cellular Biology and Pathology
College
College of Graduate Studies
First Advisor
Adviye Ergul
Second Advisor
Onder Albayram
Abstract
Palmitic acid (PA) is the most abundant saturated fatty acid in the human body, playing a critical role in multiple metabolic processes. Epidemiological studies unequivocally demonstrate that diets high in saturated fatty acids and elevated levels of palmitic acid are directly associated with diminished cognitive function. PA is sourced both from dietary intake and synthesized through de novo lipogenesis in the liver, and it possesses the remarkable ability to cross the blood-brain barrier. This capability increases the fatty acid pool within the brain, ultimately influencing cognitive health. Importantly, palmitic acid (C16:0) has been linked to severe neurodegenerative processes, most notably to the neuronal hyperphosphorylation and deposition of tau protein. Given that cerebrovascular dysfunction is one of the earliest pathologies detected in dementia, our novel hypothesis is that a PA-rich diet mediates neurovascular dysfunction in part by cerebrovascular tau hyperphosphorylation without neurodegeneration, leading to cognitive impairment. To rigorously test this hypothesis, we implemented a comprehensive approach to evaluate both physiological and cognitive functions over time, supported by lipidomic, transcriptomic, molecular, and biochemical studies. In a preclinical murine model exposed to a novel PA-rich diet, significant cerebrovascular tau phosphorylation (p-tau), neurovascular uncoupling, and behavioral dysfunction were observed as early as twelve weeks. Over time, the behavioral dysfunction progressed into cognitive impairment, coupled with sustained structural and functional cerebrovascular deficits as determined by transmission electron microscopy and Laser Doppler flowmetry. PA-rich diet didn’t promote cerebrovascular p-tau accumulation associated behavioral deficits in a global tau knockout (KO) murine model, underscoring the importance of p-tau accumulation in the cerebrovasculature. Moreover, another transgenic animal harboring the humanized tau has shown accelerated cognitive and neurovascular impairment after being on the same PA-rich diet for 12 weeks. Collectively, using a PA-rich diet in three different mouse models and integrating molecular, biochemical, and functional methodologies, we provide novel evidence that dysregulation of tau protein in the cerebrovasculature leads to structural and functional impairments, which are likely precursors to neurodegeneration.
Recommended Citation
Karakaya, Eda, "Palmitic Acid-Rich Diet Induced Cerebrovascular Tau Pathology Contributes to the Development and Progression of Cognitive Impairment" (2025). MUSC Theses and Dissertations. 1072.
https://medica-musc.researchcommons.org/theses/1072
Rights
Copyright is held by the author. All rights reserved.