Browsing by Author "Moreno, Julie A., advisor"
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Item Open Access Characterization of the Dunkin Hartley guinea pig as a non-transgenic and multimorbid model of brain aging(Colorado State University. Libraries, 2024) Glennie, Kristen Skye, author; Hamilton, Karyn L., advisor; Moreno, Julie A., advisor; LaRocca, Thomas J., committee member; Santangelo, Kelly S., committee memberAlzheimer's Disease and Alzheimer's Disease Related Dementia (AD/ADRD) affect an estimated 55 million people worldwide; a staggering figure that is expected to grow in the coming years. With this projection looming, we have yet to identify any effective cures, treatments, or preventative strategies. Historically, AD/ADRD research is conducted using genetically engineered pre-clinical models, that express a specific brain aging pathology. Recent discoveries, however, have identified a dynamic whole-body "inflammaging" phenotype that exists with, and likely contributes to, AD/ADRD onset and progression. Currently, we do not have an accessible and tractable preclinical model that naturally mimics the age-related, systemic and progressive neurodegenerative phenotype present in humans. Recent findings, however, suggest the Dunkin Hartley guinea pig (HGP) may address this need. HGPs are known to develop systemic inflammation and progressive age-related comorbidities characteristic of human aging. The presence of this whole-body aging phenotype prompted investigation into the brain. Genetic and transcriptomic analyses found aged HGPs exhibit strong sequence homology, and similar protein expression patterns to human brain aging and AD. Further, immunohistochemical assessment found aged HGPs express markers of neuroinflammation and misfolded proteins in the hippocampus. To further interrogate these novel findings, we examined the histopathology of 4 brain regions often implicated in neurodegenerative decline for evidence of progressive neuropathology. Our results identify the presence of an age related neuroinflammatory and phosphorylated tau phenotype. Findings from this study contribute to the overarching hypothesis that AD/ADRD is a whole-body disease, and ultimately support the goal of closing the existing translational gap between preclinical and clinical neurodegenerative research.Item Embargo Infectious disease, age, and environmental contaminants as neurotoxicants that modulate glia and contribute to neurodegenerative pathology(Colorado State University. Libraries, 2024) Latham, Amanda Shellee, author; Moreno, Julie A., advisor; Basaraba, Randall J., advisor; Tjalkens, Ronald B., committee member; Santangelo, Kelly S., committee member; Elf, Jessica, committee memberNeurodegenerative disease cases are expected to double over the next twenty years. These diseases, which include Alzheimer's Disease (AD) and Parkinson's Disease (PD), are incurable with a largely unknown etiology. It is acknowledged within the field that age is the greatest risk factor for neurodegenerative disease, and that genetics and environmental factors, such as neurotoxicants and infectious agents, likely play a role. Despite this knowledge, it is not entirely understood why select individuals are pushed into a state of disease, while others progress into a state of normal brain aging. This is further complicated by the shared neuropathology between brain aging and neurodegenerative disease, which includes blood-brain barrier (BBB) modulation, gliosis, misfolded protein accumulation, and loss of function or degradation of neurons. To address these gaps in our understanding, the studies herein provide valuable insight as to how infectious disease, specifically through infection with Mycobacterium tuberculosis, contributes to the progression of neuropathology, evaluates an alternative model of brain aging that better recapitulates human disease, and provides mechanistic understanding of the neuroprotective and neurotoxic roles of glia in disease. Altogether, these data elucidate the etiology and mechanisms that drive neurodegenerative disease, as well as possible therapeutic avenues that may bring us one step closer to a cure.Item Open Access Using cannabidiol and trazodone to treat protein misfolding neurodegenerative disease in C. elegans(Colorado State University. Libraries, 2022) Gilberto, Vincenzo S., author; Moreno, Julie A., advisor; Legare, Marie, committee member; McGrath, Stephanie, committee member; Popichak, Katriana, committee member; Dooley, Gregory, committee memberAlzheimer's disease is one of the most common neurodegenerative disorders and is typically characterized by the accumulation of the misfolded proteins Amyloid-Beta (Aβ1-42) and/or hyperphosphorylation of Tau (p-Tau). Despite the lack of a cure for the disease, it is well known that targeting signaling pathways involved in reactive oxygen species (ROS) or the unfolded protein response (UPR) mitigates the toxic effects of misfolded proteins, including behavioral deficits, glial inflammation, and neuronal toxicity. Laboratory animals, which have long been used to study this disease, have been genetically modified to express the two aforementioned proteins and express similar deleterious effects. However, despite the individual targeting of these pathways—although neuroprotective for some time—the laboratory model still succumbs to the disease. In this work, we hypothesized that drug-stacking Cannabidiol and Trazadone, which respectively target ROS production and UPR, would improve the neuronal function and extend the lifespan of neurodegenerative nematode models. To test this hypothesis, we utilized specific strains of C. elegans that have been genetically modified to contain the two common misfolded proteins found to aggregate in the brains of patients with Alzheimer's, Aβ1-42 and p-Tau. The AD-modeled nematodes were designed to parallel the middle- and late-stage in humans, starting at the point where signs of the disease first begin to become apparent. This research used Cannabidiol and Trazodone to inhibit ROS and UPR, respectively. Our experiments revealed that neurodegenerative C. elegans motility and lifespan significantly improved with both combination and isolated treatments of CBD and TRA. Our data also suggest that genetically susceptible neurodegenerative C. elegans can benefit from both full-life and late-stage rescue utilizing CBD and TRA. We predict these results may help guide future experimentation that incorporates the use of both CBD and TRA in higher organisms, including rodent models of neurodegeneration and aged canines with cognitive decline.