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Browsing by Author "Tjalkens, Ronald B., advisor"

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    Glial inflammatory signaling in manganese neurotoxicity
    (Colorado State University. Libraries, 2009) Moreno, Julie Ann, author; Tjalkens, Ronald B., advisor
    Degenerative movement disorders affecting the basal ganglia, including, Parkinson's (PD) and Huntington's diseases, are debilitating and currently incurable. Increased inflammatory gene expression in astrocytes promotes neuronal loss in these disorders, but the signaling mechanisms underlying this phenotype are not fully understood. In order to enhance understanding of this phenotype, the degenerative movement disorder, manganism, is a useful model, because patients suffering from excessive exposure to manganese (Mn) develop a neurodegenerative condition affecting the same brain region and with clinical features resembling PD. Recently, the potential effects of Mn on the developing brain have gained attention due to an increase in cognitive deficits with overexposure to Mn. Moreover, astrocytes are a known target of Mn, and reactive gliosis seems to precede neuronal injury. Mn toxicity enhances production of the inflammatory mediator nitric oxide (NO) in astrocytes by a mechanism involving NF-κB, the principal transcription factor responsible for expression of inducible nitric oxide synthase (NOS2). However, the role Mn toxicity plays in the developing brain along with the signaling mechanism(s) by which Mn enhances activation of NF-κB remains poorly understood in astrocytes. Therefore, in order to address the gap in knowledge I have characterized the role of glial cells in the promotion of neuronal damage in the developing and adult brain in a mouse model of Mn neurotoxicity, as well as the mechanism by which Mn enhances inflammatory activation of NF-κB dependent genes in astrocytes. First, it was identified that sGC relays signals to ERK and NF-κB, initiating NO signaling in astrocytes. Also it was determined that the glial inflammatory response leads to an age- and sex-dependent vulnerability of the basal ganglia which can be modulated by E2. This indicates that Mn toxicity in the developing brain results in locomotor deficits, reduction in normal dopaminergic neurotransmitter release, increased NOS2 expression in glial cells and neuronal injury. These findings are significant because once the mechanism of Mn-induced inflammatory activation of glial cells is understood, it will promote a better understanding of manganism and potentially other disorders of the basal ganglia.
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    Glial signaling mechanisms in the progression of neuroinflammatory injury
    (Colorado State University. Libraries, 2018) Popichak, Katriana A., author; Tjalkens, Ronald B., advisor; Bouma, Gerrit J., committee member; Goodrich, Laurie R., committee member; Legare, Marie E., committee member; McLean, Jennifer L., committee member
    The response of glial cells to foreign and endogenous stress signals is extensive. As a result, release of inflammatory factors as means of cellular communication and innate immune function, or neuroinflammation, can contribute to neurodegeneration and increased activation of surrounding glia, often associated with Parkinson's disease (PD). The identification of glial activation as an early event in the progression of neurodegenerative disease that precedes neuronal cell death presents an opportunity for better diagnostic markers, as well as new pathways that could be targeted therapeutically. The transcription factor, Nuclear Factor-kappa B (NF-κB), regulates the expression of multiple neuroinflammatory cytokines and chemokines in activated glial cells but the signaling factors modulating glial-glial and glial-neuronal signaling during neurotoxic injury are poorly understood. Thus, inhibition of NF-κB signaling in glial cells could be a promising therapeutic strategy for the prevention of neuroinflammatory injury. Recently, it was found that selected orphan nuclear receptors in the NR4A family (nerve growth factor-induced-β/NGFI-β), including NR4A1 (Nur77) and NR4A2 (Nurr1), can inhibit the inflammatory effects of NF-κB but there are no approved drugs that target these receptors. In the current studies, we utilized several experimental approaches to target neuroinflammation in cellular models of PD and manganese neurotoxicity in primary glia and in animal models. One of these studies demonstrated that a novel ligand of NR4A1 and NR4A2, 1,1-bis (3'-indolyl) -1-(p-methoxyphenyl) methane (C-DIM5), suppressed NF-κB-dependent inflammatory gene expression in astrocytes following treatment with 1-methyl-4-phenyl-1, 2, 3,6-tetrahydropyridine (MPTP) and the inflammatory cytokines, IFN-γ and TNF-α. These data were further supported by previous studies from our laboratory, which examined efficacy of multiple C-DIM compounds in PD animal and cellular models, including one (C-DIM12) identified as a modulator of Nurr1 activity that also inhibited NF-kB-dependent gene expression in glial cells. Collectively, these data demonstrate that NR4A1/Nur77 and NR4A2/Nurr1 dynamically regulated inflammatory gene expression in glia by modulating the transcriptional activity of NF-κB. An additional study examined the role of NF-κB in manganese (Mn)-induced neurotoxicity by exposing purified microglia, astrocytes (from both wild-type and an astrocyte- specific NF-kB (IKK2) knock-out (KO) mouse) and mixed glial cultures to varying Mn concentrations and then treated neurons with the conditioned media (GCM) of each cell type. In doing so, we showed that mixed glial cultures exposed to Mn enhanced glial activation and neuronal death compared to microglia, wild type astrocytes or IKK2-knockout astrocytes alone or in mixed cultures suggesting that astrocytes are a critical mediator of Mn neurotoxicity through enhanced expression of inflammatory cytokines and chemokines, including those most associated with reactive phenotype such as C3 and CCL2. Thus, these studies elucidate key mechanisms associated with neuroinflammation and present potential therapeutic targets in glial cells that regulate the progression of neuroinflammatory injury.
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    Microglial innate and adaptive immune function modulates disease pathology in and environmental pesticide model of Parkinson's disease
    (Colorado State University. Libraries, 2022) Rocha, Savannah M., author; Zabel, Mark, advisor; Tjalkens, Ronald B., advisor; Bouma, Jerry, committee member; Kading, Rebekah, committee member; Moreno, Julie, committee member
    Parkinson's Disease (PD) is the world's foremost movement disorder with pathological features including loss of dopaminergic neurons (DAn) within the substantia nigra pars compacta (SNpc), chronic activation of glial cells, and the misfolding and aggregation of a-synuclein (a-syn). Compounding evidence gathered over the past two centuries suggests environmental exposures, genetics, and aging can induce complicated cell-to-cell interactions that evoke and facilitate chronic inflammatory states; but the role that individual glial cells, in particular microglia, have in the progression of disease remains unknown. Difficulties in recapitulating the three pathological hallmarks of PD underscore the need for better animal models. To address this gap in functional investigation, the studies herein provide, for the first time, an optimized environmental exposure model with the pesticide rotenone (2.5mg/kg/day) in murine, which has proven effective at mirroring DAn degeneration, gliosis and misfolded a-syn accumulation. The pathology observed was region-, time- and dose-dependent, emphasizing the importance of environmental exposure and associated PD diagnosis. The successful optimization of this exposure model has allowed for its implementation in transgenic mice, which was previously unfeasible. To determine microglial specific innate inflammatory reactions in the progression of PD, we targeted the inflammatory transcriptional regulator NF-kB by use of transgenic CX3CR1-Cre
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    Neuroinflammation and the two-hit hypothesis of Parkinson's disease
    (Colorado State University. Libraries, 2019) Bantle, Collin M., author; Tjalkens, Ronald B., advisor; Zabel, Mark, committee member; Moreno, Julie, committee member; Kato, Takamitsu, committee member; Randall, Elissa K., committee member
    The ever-increasing prevalence of neurodegenerative diseases, Alzheimer's Disease (AD) and Parkinson's disease (PD), impose one the most significant medical and public health threats throughout the world. Characteristic PD symptoms include loss of voluntary motor control due to α-synuclein protein-aggregation, neuroinflammatory glial activation, mitochondrial dysfunction, oxidative stress, and progressive neuronal loss. There are currently no disease-modifying therapies for the disease nor has the etiology of PD been elucidated. Epidemiologic and experimental evidence suggests that genetic susceptibility, environmental pesticide exposure, and viral infections are possible risk-factors for PD, but a clear understanding of the environmental links to PD and how these factors can act in concert remains extremely limited. Research is beginning to shed light on neuroinflammation as a converging and coalescing pathway in the pathogenesis and pathophysiology of genetic, sporadic, and postencephalitic PD. While it has been appreciated since the late 1980s that brain inflammation is a hallmark of PD and other age-related neurodegenerative diseases, the immunological role of glia and the key trophic and inflammatory factors and pathways responsible for neurotoxicity and neuronal death in PD have not been clearly elucidated. Understanding how these pathways are regulated in glia during genetic, sporadic, and postencephalitic PD, and how they can directly or secondarily affect the onset and progression of PD is of keen interest. Therefore, the subject of this work will be to explore mechanisms by which glial cells modulate neuronal injury in genetic, sporadic, and postencephalitic cases of PD, with an emphasis on the role of neuroinflammatory activation of glia in single and two-hit models of PD.