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- All Subjects: neuroinflammation
- Creators: Velazquez, Ramon
- Resource Type: Text
Description
A prominent aspect of Alzheimer’s disease (AD) is the presence of neuroinflammation is mediated by the activation of microglial cells, which are the immune cells in the central nervous system (CNS) that express an array of cytokines that may promote an inflammatory response. The main cytokines produced are: tumor necrosis factor-alpha (TNF-), interleukin-1β (IL-1β), and interleukin-6 (IL-6). The presence of these cytokines in the CNS may lead to neuronal death, to the production of toxic chemicals (such as nitric oxide), and to the generation of amyloid beta (a major pathological feature of AD). Previous studies have shown that modulation of the inflammatory response in the nervous system can potentially prevent and/or delay the onset of neurodegenerative diseases such as AD. Therefore, it is important to identify the process that induces CNS inflammation. For example, mitochondrial lysates have been found to produce an inflammatory response due to their ability to stimulate TNF-, Aβ, and APP mRNA [10]. Interestingly, extracellular mitochondria have been detected in the brain due to neurons degrading old mitochondria extracellularly. Therefore, we set out to study the effect of whole mitochondria isolated by differential centrifugation from human neuroblastoma cells (BE(2)-M17 cells) on the neuroinflammatory response in a human microglia model (THP-1 cells). Despite our best efforts, in the end it was unclear whether the mitochondrial fraction or other cellular components induced the inflammatory response we observed. Thus, further work with an improved mitochondrial isolation method should be carried out to address this issue.
ContributorsStokes, Laura Jean (Author) / DeCourt, Boris (Thesis director) / Sweazea, Karen (Committee member) / Gonzales, Rayna (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Neuroinflammation contributes significantly to the pathogenesis of Alzheimer’s and Parkinson’s diseases. However, the inflammatory pathways contributing to neurodegeneration are not well understood. Moreover, there is a need to identify changes in inflammatory signaling that may occur early in disease progression to identify potential targets for therapeutic intervention. An important step towards addressing this need is understanding how the extracellular vesicles (EVs) released by microglia can be detected in the periphery. For microglia, phagocytic macrophages, and CD 14+ monocytes share many genes and membrane- bound proteins, and there is currently no method to distinguish microglia EVs from those generated by macrophages or monocytes. Therefore, this study aims to identify membrane-bound proteins unique to microglia EVs to enable their reliable isolation. Liquid-chromatography tandem mass spectrometry analysis was used to detect proteins in the EVs from both normal and disease-associated human stem-cell differentiated microglia (iMGL), and human induced pluripotent stem cell-derived CD 14+ monocytes and macrophages. We identified 23 proteins unique to the microglial EVs, eight of which localize to the membrane and may be potential targets for isolation. This investigation also used RNA sequencing to gain insight into the contents of DAM-like and control iMGL EVs and of microglia and white blood cells in Alzheimer’s disease. We propose that the contents of microglial EVs isolated from peripheral compartments will provide crucial insight for understanding the current inflammatory state of CNS microglia. This approach could provide a means to track changes in microglial activation over time, which is critical for understanding the progression of neuroinflammatory diseases like Alzheimer's and Parkinson's. Additionally, it may offer insights into potential therapeutic targets for modulating neuroinflammation.
ContributorsLopatin, Ulia (Author) / Mastroeni, Diego (Thesis director) / Velazquez, Ramon (Committee member) / Van Keuren-Jensen, Kendall (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2024-05
Description
Glyphosate is the most heavily used herbicide worldwide and recent reports indicate that it may have deleterious neurological and neurodegenerative effects on human health. Here I demonstrate that glyphosate can infiltrate the brain in a dose-dependent manner in mice sub-acutely exposed to 125, 250, or 500 mg/kg/day. I also establish that glyphosate elicits a neuroinflammatory response in both the cortex and hippocampus, marked by elevation of tumor necrosis factor α (TNFα), and causes transcriptomic dysregulation of key genes involved in oligodendrocyte proliferation, maturation, and myelination. Given that both the hippocampus and the cortex are critical for learning and memory, and are affected in Alzheimer’s disease (AD), I investigate how 50 or 500 mg/kg chronic glyphosate exposure influences locomotion, anxiety-like behavior, and cognition in the APP/PS1 mouse model of AD. Results show that while glyphosate did not influence weight, appearance, locomotion, or anxiety-like behavior, learning acquisition is impaired in the place preference and reaction time tasks following 500mg/kg chronic exposure. Additionally, I report a strong increase in water consumption in glyphosate-exposed mice, demonstrating that chronic glyphosate exposure induces polydipsia. To ascertain whether glyphosate influences AD pathogenesis, I examine neuropathological changes following chronic daily oral exposure to 50 or 500 mg/kg glyphosate. Post-mortem analysis of amyloid-beta (Aβ) in APP/PS1 hippocampal and cortical tissue show that 50 or 500 mg/kg of glyphosate elevates soluble and insoluble Aβ1-40 and Aβ1-42 in both sexes, with females showing higher levels. Further analysis of cortical TNFα levels in chronically exposed APP/PS1 mice and littermate controls confirms a neuroinflammatory response. I report no differences in amyloid precursor protein (APP) processing pathway components, CA1 NeuN+ neuronal number, relative density of Iba1+ microglia in the hippocampus, or relative density of MBP+ oligodendrocytes in the fimbria. I also show that 50mg/kg chronic glyphosate exposure elevates hemoglobin A1c levels, indicating disruptions in glucose metabolism that may be tied to polydipsia. Collectively, these results indicate that glyphosate crosses the blood-brain barrier, induces a neuroinflammatory response, and exacerbates amyloid pathology. Ultimately, these findings provide important insight into the concerns surrounding the neurological implications of glyphosate exposure.
ContributorsWinstone, Joanna (Author) / Velazquez, Ramon (Thesis advisor) / Newbern, Jason M (Committee member) / Huentelman, Matthew J (Committee member) / Leung, Maxwell (Committee member) / Coleman, Paul D (Committee member) / Arizona State University (Publisher)
Created2023