TY  - GEN
A1  - Stapper, Zeenna A.
TI  - The role of redox homeostasis in Drosophila models of Aß aggregation
N2  - 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 (A?) 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 A? 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 A?42
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 A?42 by an increase in glutathione
redox potential but glia cells are not susceptible for this insult caused by toxic A?42. The glutathione redox
imbalance already occurs at an early time point of A? deposition and is only observable in toxic A?42-
expressing flies but not in flies expressing the less toxic TandemA?40 variant. Most notably, I show that
modifications of glutathione synthesis directly modulate A?42-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 A?42-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 A?42-induced neurotoxicity.
AV  - public
ID  - heidok24197
Y1  - 2019///
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/24197/
ER  -