Browsing by Author "Thang, Morrent"

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    Circulating HMGB1 is elevated in veterans with Gulf War Illness and triggers the persistent pro-inflammatory microglia phenotype in male C57Bl/6J mice
    (Springer Nature, 2021-07-12) Garza-Lombó, Carla; Thang, Morrent; Greve, Hendrik J.; Mumaw, Christen L.; Messenger, Evan J.; Ahmed, Chandrama; Quinn, Emily; Sullivan, Kimberly; Block, Michelle L.; Pharmacology and Toxicology, School of Medicine
    Gulf War Illness (GWI) is a chronic, multi-symptom peripheral and CNS condition with persistent microglial dysregulation, but the mechanisms driving the continuous neuroimmune pathology are poorly understood. The alarmin HMGB1 is an autocrine and paracrine pro-inflammatory signal, but the role of circulating HMGB1 in persistent neuroinflammation and GWI remains largely unknown. Using the LPS model of the persistent microglial pro-inflammatory response, male C57Bl/6J mice injected with LPS (5 mg/kg IP) exhibited persistent changes in microglia morphology and elevated pro-inflammatory markers in the hippocampus, cortex, and midbrain 7 days after LPS injection, while the peripheral immune response had resolved. Ex vivo serum analysis revealed an augmented pro-inflammatory response to LPS when microglia cells were cultured with the 7-day LPS serum, indicating the presence of bioactive circulating factors that prime the microglial pro-inflammatory response. Elevated circulating HMGB1 levels were identified in the mouse serum 7 days after LPS administration and in the serum of veterans with GWI. Tail vein injection of rHMGB1 in male C57Bl/6 J mice elevated TNFα mRNA levels in the liver, hippocampus, and cortex, demonstrating HMGB1-induced peripheral and CNS effects. Microglia isolated at 7 days after LPS injection revealed a unique transcriptional profile of 17 genes when compared to the acute 3 H LPS response, 6 of which were also upregulated in the midbrain by rHMGB1, highlighting a distinct signature of the persistent pro-inflammatory microglia phenotype. These findings indicate that circulating HMGB1 is elevated in GWI, regulates the microglial neuroimmune response, and drives chronic neuroinflammation that persists long after the initial instigating peripheral stimulus.
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    Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction
    (Hindawi, 2017) Hiday, Andrew C.; Edler, Michael C.; Salek, Asma B.; Morris, Cameron W.; Thang, Morrent; Rentz, Tyler J.; Rose, Kristie L.; Jones, Lisa M.; Baucum, Anthony J., II; Biology, School of Science
    Signaling changes that occur in the striatum following the loss of dopamine neurons in the Parkinson disease (PD) are poorly understood. While increases in the activity of kinases and decreases in the activity of phosphatases have been observed, the specific consequences of these changes are less well understood. Phosphatases, such as protein phosphatase 1 (PP1), are highly promiscuous and obtain substrate selectivity via targeting proteins. Spinophilin is the major PP1-targeting protein enriched in the postsynaptic density of striatal dendritic spines. Spinophilin association with PP1 is increased concurrent with decreases in PP1 activity in an animal model of PD. Using proteomic-based approaches, we observed dopamine depletion-induced decreases in spinophilin binding to multiple protein classes in the striatum. Specifically, there was a decrease in the association of spinophilin with neurofilament medium (NF-M) in dopamine-depleted striatum. Using a heterologous cell line, we determined that spinophilin binding to NF-M required overexpression of the catalytic subunit of protein kinase A and was decreased by cyclin-dependent protein kinase 5. Functionally, we demonstrate that spinophilin can decrease NF-M phosphorylation. Our data determine mechanisms that regulate, and putative consequences of, pathological changes in the association of spinophilin with NF-M that are observed in animal models of PD.
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    The bidirectional lung brain-axis of amyloid-β pathology: ozone dysregulates the peri-plaque microenvironment
    (Oxford University Press, 2023) Greve, Hendrik J.; Dunbar, August L.; Garza Lombo, Carla; Ahmed, Chandrama; Thang, Morrent; Messenger, Evan J.; Mumaw, Christen L.; Johnson, James A., Jr.; Kodavanti, Urmila P.; Oblak, Adrian L.; Block, Michelle L.; Pharmacology and Toxicology, School of Medicine
    The mechanisms underlying how urban air pollution affects Alzheimer's disease (AD) are largely unknown. Ozone (O3) is a reactive gas component of air pollution linked to increased AD risk, but is confined to the respiratory tract after inhalation, implicating the peripheral immune response to air pollution in AD neuropathology. Here, we demonstrate that O3 exposure impaired the ability of microglia, the brain's parenchymal immune cells, to associate with and form a protective barrier around Aβ plaques, leading to augmented dystrophic neurites and increased Aβ plaque load. Spatial proteomic profiling analysis of peri-plaque proteins revealed a microenvironment-specific signature of dysregulated disease-associated microglia protein expression and increased pathogenic molecule levels with O3 exposure. Unexpectedly, 5xFAD mice exhibited an augmented pulmonary cell and humoral immune response to O3, supporting that ongoing neuropathology may regulate the peripheral O3 response. Circulating HMGB1 was one factor upregulated in only 5xFAD mice, and peripheral HMGB1 was separately shown to regulate brain Trem2 mRNA expression. These findings demonstrate a bidirectional lung-brain axis regulating the central and peripheral AD immune response and highlight this interaction as a potential novel therapeutic target in AD.