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dc.contributor.authorJohnson, Victor Johnnie
dc.date.accessioned2014-03-04T21:59:02Z
dc.date.available2014-03-04T21:59:02Z
dc.date.issued2002-08
dc.identifier.otherjohnson_victor_j_200208_phd
dc.identifier.urihttp://purl.galileo.usg.edu/uga_etd/johnson_victor_j_200208_phd
dc.identifier.urihttp://hdl.handle.net/10724/29212
dc.description.abstractAluminum is a ubiquitously present metal with no known physiological role. Nevertheless, abnormally high brain aluminum levels are evident in the brains of patients with neurodegenerative diseases including Alzheimer’s disease. Epidemiological studies have linked high levels of aluminum in the drinking water with an increased risk of both disease and non-disease dementia and cognitive loss. The objectives of the present studies were to define the role of immune effector functions in aluminum-induced disruption of neuron-glial interactions. Aluminum has been shown to induce the expression of tumor necrosis factor á (TNFá) in the cerebrum of mice and also in human glioblastoma cells in culture. We show here that aluminum as AlCl3 markedly reduced the production of TNFá in murine microglial cells. This effect was mediated by the production of reactive oxygen species (ROS) and lipid peroxidation since antioxidant treatment prevented the effects. This study indicates that oxidative stress is an integral component of aluminum neurotoxicity. Neuron-like cells were also affected by aluminum. Treatment of PC-12 cells with AlCl3 resulted in a loss of membrane fluidity concomitant with increased proton extrusion and aberrant membrane physiology including hyperpolarization. These effects were related to an increase in ROS production. Aluminum maltolate (Al-malt), a lipophilic complex of aluminum was more toxic. Apoptosis and necrosis were induced by Al-malt in Neuro-2a cells. Cell death induced by Al-malt was dependent on de novo protein synthesis but not on major kinase pathways. In addition, alterations of calcium homeostasis may also be involved. Interestingly, leakage of cytoplasmic protein was evident even in cell dying by apoptosis and indicates that neuronal death may activate secondary inflammation leading to further neurodegeneration. Al-malt cytotoxicity in rotation-mediated aggregate cultures was correlated with an increase in pro-inflammatory cytokine expression and a marked decrease in neurotrophin expression. An alteration of the cytokine/neurotrophin balance may be central to the etiopathogenesis of aluminum neurotoxicity. Overall the results of these studies further strengthen the role of oxidative stress in aluminum neurotoxicity. We have also identified a new mechanism by which aluminum can damage the brain, deregulation of the cytokine/neurotrophin balance. Alterations in this balance may also exist in human neurodegenerative diseases.
dc.languageAluminum neurotoxicity involves oxidative stress, inflammation and apoptosis : implications for neurodegeneration
dc.publisheruga
dc.rightspublic
dc.subjectAluminum
dc.subjectNeurodegeneration
dc.subjectTNF 
dc.subjectInflammation;
dc.subjectNeurotrophin
dc.subjectNeurotoxicity
dc.subjectOxidative stress
dc.titleAluminum neurotoxicity involves oxidative stress, inflammation and apoptosis : implications for neurodegeneration
dc.typeDissertation
dc.description.degreePhD
dc.description.departmentPhysiology and Pharmacology
dc.description.majorToxicology
dc.description.advisorRaghubir P. Sharma
dc.description.committeeRaghubir P. Sharma
dc.description.committeeThomas F. Murray
dc.description.committeeGaylen L. Edwards
dc.description.committeeDonald L. Evans
dc.description.committeePhillip L. Williams


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