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Abstract

There is accumulating evidence that Alzheimer´s Disease (AD) pathogenesis correlates with increased oxidative stress due to the overproduction of reactive oxygen species (ROS) and decrease in antioxidant defense systems. Several cellular insults increasing oxidative stress in AD include mitochondrial dysfunction, inflammation and the accumulation of oxidative stress markers. Developing genetic in vivo models to study the impact of redox homeostasis on amyloid-beta (Aβ) neurotoxicity and to decipher whether changes in redox balance are a cause or consequence of AD pathology is of high importance. Here, I present ‘newly established’ in vivo models to study the role of redox homeostasis in AD. Therefore, I combine genetically encoded redox sensors with Drosophila models of Aβ aggregation. Thereby, I focus on two major regulators of the redox homeostasis. On the one hand, hydrogen peroxide (H2O2), a nonradical oxidant and major ROS that possesses cytotoxic effects and is an important signaling molecule. And on the other hand, I focus on glutathione, a low molecular weight thiol, which represents one of the two major Nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reducing systems in the cell that holds protective effects against oxidative damage. In this thesis, I aim to provide new insights into a better characterization and understanding of the impact of changes in redox homeostasis and the involvement of stress responsive pathways in the onset and progression of AD. The main finding of this study is that changes in glutathione redox potential are linked to Aβ42 neurotoxicity. I have found that the common notion of ‘oxidative stress‘ driven neurodegeneration is specifically mediated by changes in the neuronal glutathione redox potential rather than the increasing levels of H2O2. Interestingly, neurons respond to the deposition of Aβ42 by an increase in glutathione redox potential but glia cells are not susceptible for this insult caused by toxic Aβ42. The glutathione redox imbalance already occurs at an early time point of Aβ deposition and is only observable in toxic Aβ42- expressing flies but not in flies expressing the less toxic TandemAβ40 variant. Most notably, I show that modifications of glutathione synthesis directly modulate Aβ42-mediated neurotoxicity, in parallel to an increase in the c-Jun N-terminal kinase (JNK) stress signaling response. Intriguingly, an increase in glutathione synthesis is not beneficial in this AD disease model, but exacerbates Aβ42-mediated toxicity. While recent studies point towards the important role of redox signaling processes being the driving force in many human diseases, main novelty of this thesis is the development of genetic in vivo tools to selectively analyze changes in redox homeostasis associated with AD pathomechanisms. To summarize, I hereby provide in vivo evidence of the central role of glutathione redox homeostasis in early AD pathogenesis and progression. Furthermore, I examine early events of neuronal dysregulation and disease onset and further offer a screening platform for possible disease modifying therapies. Most importantly, this study proposes additional roles of glutathione beyond the generic neuroprotective antioxidant and being involved in the Aβ42-induced neurotoxicity.