Browsing by Author "Santangelo, Kelly S., committee member"
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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 Embargo Targeting proteostatic maintenance and mitochondrial function with phytochemical compounds in models of brain and skeletal muscle aging(Colorado State University. Libraries, 2024) Walsh, Maureen Ann, author; Hamilton, Karyn L., advisor; Fling, Brett W., committee member; Moreno, Julie A., committee member; LaRocca, Thomas J., committee member; Santangelo, Kelly S., committee memberThere is a growing population of older adults (>65+ years) worldwide that is projected to increase in coming decades, presenting both a challenge and an opportunity. Specifically, age is the number one risk factor for chronic diseases like sarcopenia, the loss of muscle mass and function, and neurodegenerative diseases such as Alzheimer's Disease. The twelve hallmarks of aging are a collection of cellular changes that drive the aging process. Two highly interconnected hallmarks of aging that drive the development and progression of sarcopenia and neurodegeneration are loss of proteostasis (protein homeostasis) and mitochondrial dysfunction. While progress has been made in understanding the etiology of chronic diseases, treatments for age-related chronic diseases affecting skeletal muscle and the brain are lacking. One reason for the lack of effective treatments in humans is the absence of preclinical animal models that recapitulate human aging. However, our group previously identified the Hartley guinea pig as a novel model of brain and skeletal muscle aging. We then treated these guinea pigs with a phytochemical compound to delay the onset and/or slow the progression of brain and skeletal muscle aging. Through the experiments in this dissertation, I observed that: 1.) phytochemical compounds, branded as Protandim, can improve mechanisms of proteostasis independent of changes in mitochondrial respiration in muscle precursor cells; 2.) the phytochemical compound, branded as PB125, can improve mechanisms of skeletal muscle proteostasis in the Hartley guinea pig; 3.) PB125 can also decrease neuroinflammation in the Hartley guinea pig; and 4.) despite the lack of declines in hippocampal mitochondrial respiration with age, Hartley guinea pigs exhibit decreased mitochondrial efficiency. Collectively, this dissertation builds on prior work suggesting that the Hartley guinea pig is a valuable model to test preclinical interventions.Item Open Access Targeting skeletal muscle mitochondrial function with a Nrf2 activator in a novel model of musculoskeletal decline(Colorado State University. Libraries, 2020) Musci, Robert Vincent, author; Hamilton, Karyn L., advisor; Hickey, Matthew S., committee member; Lark, Daniel S., committee member; Santangelo, Kelly S., committee memberThis dissertation describes a series of three experiments with an overall objective to understand how targeting mitochondrial function with a phytochemical Nrf2 activator can prevent the onset of or mitigate the progression of mitochondrial dysfunction and sarcopenia in a novel model of musculoskeletal aging. The specific aims of the three experiments were to 1) characterize the age-related changes in skeletal muscle in Dunkin-Hartley guinea pigs; 2) assess the effect of Nrf2 activator treatment on skeletal muscle energetics by measuring mitochondrial function; and 3) determine how Nrf2 activator treatment influences components of skeletal muscle proteostasis. Dunkin-Hartley guinea pigs exhibit several characteristics reflective of human musculoskeletal aging including a decline in the proportion of type II muscle fibers, a shift towards a smaller myofiber size distribution, and a decline in muscle density in the gastrocnemius, as well as a decline in protein synthesis in both the soleus and gastrocnemius. In the second experiment, Nrf2 activator treatment improved mitochondrial respiration in both 5- and 15-month-old male and female guinea pigs. Moreover, Nrf2 activator treatment attenuated the age-related decline in mitochondrial respiration. In the third experiment, Nrf2 activator treatment attenuated the age-related decline in protein synthesis in Dunkin-Hartley guinea pigs. Altogether, these data demonstrate 1) Dunkin-Hartley guinea pigs experience age-related changes in skeletal muscle consistent with the aged musculoskeletal phenotype in humans 2) this phytochemical Nrf2 activator can improve mitochondrial function and 3) targeting mitochondrial dysfunction is an efficacious intervention to mitigate age-related declines in components of proteostasis in skeletal muscle and improve overall musculoskeletal function.Item Open Access The evaluation of myofiber remodeling and skeletal muscle inflammaging using a novel guinea pig model(Colorado State University. Libraries, 2020) Walsh, Maureen Ann, author; Hamilton, Karyn L., advisor; Lark, Daniel S., committee member; Reiser, Raoul F., II, committee member; Santangelo, Kelly S., committee memberApproximately 40% of total body mass is accounted for by the musculoskeletal system and thus, when it becomes dysfunctional it strongly influences whole body function. Sarcopenia is one facet of musculoskeletal aging and contributes to other age-related chronic diseases. Aging is a major risk factor for osteoarthritis, which is characterized by a concomitant loss of skeletal muscle, further contributing to decreased mobility. Age-related increases in low-grade inflammation and oxidative stress, referred to as the "inflammaging" phenotype, is common to both osteoarthritis and sarcopenia. While we have begun to understand the underlying pathology of sarcopenia, treatments are still lacking. One barrier to progress in identifying treatments is lack of a preclinical model that recapitulates the human skeletal muscle aging phenotype. Dunkin Hartley guinea pigs rapidly and spontaneously develop primary osteoarthritis beginning at about 4 months of age. The purpose of these studies was to determine if the Dunkin Hartley guinea pig can serve as a model to understand human skeletal muscle aging. Thus, we speculate that the Dunkin Hartley guinea pig may also be a valuable model of myofiber remodeling and skeletal muscle inflammaging. We compared skeletal muscle myofiber properties of the gastrocnemius and soleus from 5, 9, and 15-month Dunkin Hartley guinea pigs. We also compared these changes to a strain of guinea pig, Strain 13, that does not develop knee osteoarthritis at an early age. Additionally, in a second study, we assessed markers of skeletal muscle inflammation, oxidatively modified proteins, and redox signaling in 5 and 15-month Dunkin Hartley guinea pigs. The Dunkin Hartley guinea pig showed evidence of skeletal muscle aging including declines in gastrocnemius density and a shift in myofiber size distribution to encompass a greater percentage of smaller myofibers in both the gastrocnemius and soleus. Male Dunkin Hartley guinea pigs experience a trend to decrease Nrf2 protein content from 5 to 15-months implying altered redox signaling, while female Dunkin Hartley guinea pigs experienced a significant increase from 5 to 15-months. Skeletal muscle myofiber remodeling, a component of musculoskeletal aging, influences both muscle function and quality of life. Based on these analyses, Dunkin Hartley guinea pigs appear to be a potentially valuable model of musculoskeletal aging.