- Browse by Author
Browsing by Author "Ahmed, Chandrama"
Now showing 1 - 6 of 6
Results Per Page
Sort Options
Item Aspergillus versicolor Inhalation Triggers Neuroimmune, Glial, and Neuropeptide Transcriptional Changes(Sage, 2021) Ladd, Thatcher B.; Johnson, James A., Jr.; Mumaw, Christen L.; Greve, Hendrik J.; Xuei, Xiaoling; Simpson, Ed; Barnes, Mark A.; Green, Brett J.; Croston, Tara L.; Ahmed, Chandrama; Lemons, Angela; Beezhold, Donald H.; Block, Michelle L.; Medical and Molecular Genetics, School of MedicineIncreasing evidence associates indoor fungal exposure with deleterious central nervous system (CNS) health, such as cognitive and emotional deficits in children and adults, but the specific mechanisms by which it might impact the brain are poorly understood. Mice were exposed to filtered air, heat-inactivated Aspergillus versicolor (3 × 105 spores), or viable A. versicolor (3 × 105 spores) via nose-only inhalation exposure 2 times per week for 1, 2, or 4 weeks. Analysis of cortex, midbrain, olfactory bulb, and cerebellum tissue from mice exposed to viable A. versicolor spores for 1, 2, and 4 weeks revealed significantly elevated pro-inflammatory (Tnf and Il1b) and glial activity (Gdnf and Cxc3r1) gene expression in several brain regions when compared to filtered air control, with the most consistent and pronounced neuroimmune response 48H following the 4-week exposure in the midbrain and frontal lobe. Bulk RNA-seq analysis of the midbrain tissue confirmed that 4 weeks of A. versicolor exposure resulted in significant transcriptional enrichment of several biological pathways compared to the filtered air control, including neuroinflammation, glial cell activation, and regulation of postsynaptic organization. Upregulation of Drd1, Penk, and Pdyn mRNA expression was confirmed in the 4-week A. versicolor exposed midbrain tissue, highlighting that gene expression important for neurotransmission was affected by repeated A. versicolor inhalation exposure. Taken together, these findings indicate that the brain can detect and respond to A. versicolor inhalation exposure with changes in neuroimmune and neurotransmission gene expression, providing much needed insight into how inhaled fungal exposures can affect CNS responses and regulate neuroimmune homeostasis.Item 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 MedicineGulf 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.Item Continuous characterization of universal invertible amplifier using source noise(2017-12) Ahmed, Chandrama; Yoshida, Ken; Berbari, Edward; Salama, PaulWith passage of time and repeated usage of a system, component values that make up the system parameters change, causing errors in its functional output. In order to ensure the fidelity of the results derived from these systems it is thus very important to keep track of the system parameters while being used. This thesis introduces a method for tracking the existing system parameters while the system was being used using the inherent noise of its signal source. Kalman filter algorithm is used to track the inherent noise response to the system and use that response to estimate the system parameters. In this thesis this continuous characterization scheme has been used on a Universal Invertible Amplifier (UIA). Current biomedical research as well as diagnostic medicine depend a lot on shape profile of bio-electric signals of different sources, for example heart, muscle, nerve, brain etc. making it very important to capture the different event of these signals without the distortion usually introduced by the filtering of the amplifier system. The Universal Invertible Amplifier extracts the original signal in electrodes by inverting the filtered and compressed signal while its gain bandwidth profile allows it to capture from the entire bandwidth of bioelectric signals. For this inversion to be successful the captured compressed and filtered signals needs to be inverted with the actual system parameters that the system had during capturing the signals, not its original parameters. The continuous characterization scheme introduced in this thesis is aimed at knowing the system parameters of the UIA by tracking the response of its source noise and estimating its transfer function from that. Two types of source noises have been tried out in this method, an externally added noise that was digitally generated and a noise that inherently contaminates the signals the system is trying to capture. In our cases, the UIA was used to capture nerve activity from vagus nerve where the signal was contaminated with electrocardiogram signals providing us with a well-defined inherent noise whose response could be tracked with Kalman Filter and used to estimate the transfer function of UIA. The transfer function estimation using the externally added noise did not produce good results but could be improved by means that can be explored as future direction of this project. However continuous characterization using the inherent noise, a bioelectric signal, was successful producing transfer function estimates with minimal error. Thus this thesis was successful to introduce a novel approach for system characterization using bio-signal contamination.Item Peripheral HMGB1 is linked to O3 pathology of disease‐associated astrocytes and amyloid(Wiley, 2024) Ahmed, Chandrama; Greve, Hendrik J.; Garza-Lombo, Carla; Malley, Jamie A.; Johnson, James A., Jr.; Oblak, Adrian L.; Block, Michelle L.; Pharmacology and Toxicology, School of MedicineIntroduction: Ozone (O3) is an air pollutant associated with Alzheimer's disease (AD) risk. The lung-brain axis is implicated in O3-associated glial and amyloid pathobiology; however, the role of disease-associated astrocytes (DAAs) in this process remains unknown. Methods: The O3-induced astrocyte phenotype was characterized in 5xFAD mice by spatial transcriptomics and proteomics. Hmgb1fl/fl LysM-Cre+ mice were used to assess the role of peripheral myeloid cell high mobility group box 1 (HMGB1). Results: O3 increased astrocyte and plaque numbers, impeded the astrocyte proteomic response to plaque deposition, augmented the DAA transcriptional fingerprint, increased astrocyte-microglia contact, and reduced bronchoalveolar lavage immune cell HMGB1 expression in 5xFAD mice. O3-exposed Hmgb1fl/fl LysM-Cre+ mice exhibited dysregulated DAA mRNA markers. Discussion: Astrocytes and peripheral myeloid cells are critical lung-brain axis interactors. HMGB1 loss in peripheral myeloid cells regulates the O3-induced DAA phenotype. These findings demonstrate a mechanism and potential intervention target for air pollution-induced AD pathobiology. Highlights: Astrocytes are part of the lung-brain axis, regulating how air pollution affects plaque pathology. Ozone (O3) astrocyte effects are associated with increased plaques and modified by plaque localization. O3 uniquely disrupts the astrocyte transcriptomic and proteomic disease-associated astrocyte (DAA) phenotype in plaque associated astrocytes (PAA). O3 changes the PAA cell contact with microglia and cell-cell communication gene expression. Peripheral myeloid cell high mobility group box 1 regulates O3-induced transcriptomic changes in the DAA phenotype.Item 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 MedicineThe 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.Item The Role of the Lung-Brain Axis in the Ozone-Impaired Amyloid Associated Astrocytic and Vascular Phenotype(2024-06) Ahmed, Chandrama; Oblak, Adrian; Block, Michelle; Baucum, A. J.; Bissel, Stephanie J.; Nass, Richard M.Air pollution has been associated with an increased risk of Alzheimer’s Disease (AD). Studies show ozone (O3), a major component of urban air pollution, can exacerbate amyloid pathology. However, O3 reacts in its entirety with lung epithelial lining after inhalation, hence does not translocate to brain. Studies have implicated the lung−brain axis in O3 induced central nervous system (CNS) pathology. However, the mechanistic underpinnings of its role in amyloid pathology is obscure. Here, we explored the impact of O3 on the astrocytic and vascular response to amyloid plaque in 5xFAD mice and its link to the O3 lung response. O3 exposure increased GFAP positive astrocyte density correlating with increased plaque burden in the cortex. Focusing on the plaque microenvironment, we found O3 qualitatively altered plaque associated astrocytes, evidenced by both proteomic and transcriptomic changes. Along with loss of protein expression, proteomic changes reflected increased cell-cell interaction in plaque microenvironment. Specifically, we found increased astrocyte-microglia contact selectively in periplaque space from O3 exposure. Transcriptional analysis of periplaque astrocytes revealed an accelerated shift towards disease associated astrocyte (DAA) phenotype. Elevated circulating HMGB1 was previously found from O3 exposure. In this study we demonstrate deleting HMGB1 selectively in peripheral myeloid cells and not in CNS microglia ameliorates the lung immune response to O3 as well as downregulates DAA marker in the CNS, providing a potential link between peripheral HMGB1 and O3 induced astrocytic dysregulation. On examining vascular response to O3 we found increased vascular amyloid accumulation associated with an altered vascular proteomic profile. Our analysis indicates O3 potentially disrupts vascular function such as amyloid clearance. Taken together, our study demonstrates that astrocyte and neurovasculature are contributors to O3 lung-brain axis with important implications towards amyloid pathology progression and identifies peripheral myeloid HMGB1 as its potential modulator. Further studies are required to fully understand the consequences of this impact and its role in amyloid pathology.