<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "The role of redox homeostasis in Drosophila models of Aß aggregation"^^ . "There is accumulating evidence that Alzheimer´s Disease (AD) pathogenesis correlates with increased\r\noxidative stress due to the overproduction of reactive oxygen species (ROS) and decrease in antioxidant\r\ndefense systems. Several cellular insults increasing oxidative stress in AD include mitochondrial\r\ndysfunction, inflammation and the accumulation of oxidative stress markers. Developing genetic in vivo\r\nmodels to study the impact of redox homeostasis on amyloid-beta (Aβ) neurotoxicity and to decipher\r\nwhether changes in redox balance are a cause or consequence of AD pathology is of high importance.\r\nHere, I present ‘newly established’ in vivo models to study the role of redox homeostasis in AD. Therefore,\r\nI combine genetically encoded redox sensors with Drosophila models of Aβ aggregation. Thereby, I focus\r\non two major regulators of the redox homeostasis. On the one hand, hydrogen peroxide (H2O2), a nonradical\r\noxidant and major ROS that possesses cytotoxic effects and is an important signaling molecule.\r\nAnd on the other hand, I focus on glutathione, a low molecular weight thiol, which represents one of the\r\ntwo major Nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reducing systems in the\r\ncell that holds protective effects against oxidative damage. In this thesis, I aim to provide new insights into\r\na better characterization and understanding of the impact of changes in redox homeostasis and the\r\ninvolvement of stress responsive pathways in the onset and progression of AD.\r\nThe main finding of this study is that changes in glutathione redox potential are linked to Aβ42\r\nneurotoxicity. I have found that the common notion of ‘oxidative stress‘ driven neurodegeneration is\r\nspecifically mediated by changes in the neuronal glutathione redox potential rather than the increasing\r\nlevels of H2O2. Interestingly, neurons respond to the deposition of Aβ42 by an increase in glutathione\r\nredox potential but glia cells are not susceptible for this insult caused by toxic Aβ42. The glutathione redox\r\nimbalance already occurs at an early time point of Aβ deposition and is only observable in toxic Aβ42-\r\nexpressing flies but not in flies expressing the less toxic TandemAβ40 variant. Most notably, I show that\r\nmodifications of glutathione synthesis directly modulate Aβ42-mediated neurotoxicity, in parallel to an\r\nincrease in the c-Jun N-terminal kinase (JNK) stress signaling response. Intriguingly, an increase in\r\nglutathione synthesis is not beneficial in this AD disease model, but exacerbates Aβ42-mediated toxicity.\r\nWhile recent studies point towards the important role of redox signaling processes being the driving force\r\nin many human diseases, main novelty of this thesis is the development of genetic in vivo tools to\r\nselectively analyze changes in redox homeostasis associated with AD pathomechanisms. To summarize, I\r\nhereby provide in vivo evidence of the central role of glutathione redox homeostasis in early AD\r\npathogenesis and progression. Furthermore, I examine early events of neuronal dysregulation and disease\r\nonset and further offer a screening platform for possible disease modifying therapies. Most importantly,\r\nthis study proposes additional roles of glutathione beyond the generic neuroprotective antioxidant and\r\nbeing involved in the Aβ42-induced neurotoxicity."^^ . "2019" . . . . . . . "Zeenna A."^^ . "Stapper"^^ . "Zeenna A. Stapper"^^ . . . . . . "The role of redox homeostasis in Drosophila models of Aß aggregation (PDF)"^^ . . . "Zeenna A Stapper Doktorarbeit 2018.pdf"^^ . . . "The role of redox homeostasis in Drosophila models of Aß aggregation (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "The role of redox homeostasis in Drosophila models of Aß aggregation (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "The role of redox homeostasis in Drosophila models of Aß aggregation (Other)"^^ . . . . . . "preview.jpg"^^ . . . "The role of redox homeostasis in Drosophila models of Aß aggregation (Other)"^^ . . . . . . "medium.jpg"^^ . . . "The role of redox homeostasis in Drosophila models of Aß aggregation (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #24197 \n\nThe role of redox homeostasis in Drosophila models of Aß aggregation\n\n" . "text/html" . .