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The role of neuroinflammatory NF-KB signaling and glial crosstalk in neurodegeneration




Kirkley, Kelly Sullivan, author
Tjalkens, Ronald, advisor
Avery, Anne, committee member
Legare, Marie, committee member
Hanneman, William, committee member

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Neuroinflammation or inflammatory activation of astrocytes and microglia are considered pathological hallmarks and important mechanisms in debilitating neurodegenerative diseases. However, the signaling mechanisms underlying these neuroinflammatory changes are not fully understood and there is evidence that these inflammatory responses can serve both neuroprotective and neurotoxic roles. Few studies have begun to study the complicated communications occurring between activated glia and the contributions of these cells to neuronal injury. Furthermore, the importance of these pathways in environmentally relevant animal models is currently unknown. Therefore, in order to address these knowledge gaps, I utilized three different neurodegenerative diseases models, domoic acid induced seizures in sea lions, a mouse model of Parkinson's disease (PD), and an in vitro astrocyte-microglia culture model of Manganism, to decipher the contributions of microglia and astrocytes to neuronal injury and the pathways that dictate these responses. First, for the first time, I have identified significant correlations between severity of neuronal loss and glial activation in domoic acid exposed sea lions that were associated with significant changes in glutamate metabolism. This indicates that neuroinflammation is playing a never before described role in this disease and targeting this neuroinflammation may be a new source to limit progression of seizures in these animals. Secondly, by creating a mouse with an astrocyte specific deletion of the nuclear factor kappa B (NFκB) pathway, it was determined that neuroinflammatory activation of astrocytes through NFκB is important in the initiation and progression of dopaminergic cell loss in a chemical PD model. Also, in a similar model of disease, we found that full and potent activation of astrocytes to the basal ganglia toxicant manganese (Mn) required soluble factors from Mn activated microglia. These studies indicate that glial release of inflammatory factors is not only affecting neuronal function and survival, but is important in glial crosstalk and resultant exacerbation of the inflammatory response. Targeting these glial interactions may play important roles in developing treatments to limit the neurotoxicity of neuroinflammation.


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