ORCID ID
Graduation Date
Spring 5-10-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Neuroscience
First Advisor
Kelly Stauch
Abstract
The study of the intricate molecular mechanisms behind the pathology of neurodegenerative diseases has become a primary research area in the past decades. The major branches of these studies involve both disease progression and disease pathogenesis, in which neuroscientists have studied, and continue to study, the role that mitochondrial dysfunction, aberrant protein aggregation (like Tau), and immune cell reactions have on these. However, more recent studies have shined light to the fact that these three pathological features are not independent from one another and that their synchronous contributions may be the ultimate driver of neurodegeneration. This dissertation encompasses four different studies using preclinical animal models of different neurodegenerative disorders to better understand the underlying molecular mechanisms behind neurodegeneration. We tested the overarching hypothesis that both mitochondrial dysfunction and aberrant protein accumulation (like Tau) will be present in different models of neurodegenerative conditions and that the relationship between these two is a relevant contributor to disease progression. Throughout the results chapters from this dissertation, we provide evidence for the presence of not just mitochondrial dysfunction and aberrant protein accumulation, but also of neuroinflammation as a key addition to these pathologies responding to the brain damage induced by neurodegeneration. We propose the existence of two primary positive feedback loops: – Mitochondrial dysfunction and aberrant protein accumulation – Mitochondrial dysfunction and neuroinflammation – as central drivers of disease progression. The findings presented in this dissertation uncover the relationships that exist between these three primary pathologies and how they synergistically interact to accelerate the progression of neurodegenerative disease. These interconnected pathways suggest that targeting one pathology alone may not be sufficient for therapeutic intervention, and that a multi-targeted approach addressing mitochondrial dysfunction, protein aggregation, and neuroinflammation may provide more effective strategies for halting or slowing disease progression.
Recommended Citation
Estrella, Luis D., "Neurodegenerative Disease Mechanisms: Mitochondrial Impairment, Tau Aggregation, and Neuroinflammation as Central Drivers of Disease Progression" (2025). Theses & Dissertations. 913.
https://digitalcommons.unmc.edu/etd/913
Comments
2025 Copyright, the authors