Patients of Alzheimer’s Disease (AD) showed reduced levels of the actin-binding protein Drebrin in their neurons. The here presented work was set out to analyse the interaction between Drebrin and the disease-associated peptide Amyloid-β. To analyse the interaction in vivo two novel models were designed, employing the nematode C. elegans. The Amyloid-β pathology was modelled by overexpressing the disease causing peptide pan-neuronally and employing a genetic sub-stoichiometric labelling method to be able to follow the aggregation in vivo and in situ in a non-invasive manner. A second model, expressing human Drebrin pan-neuronally was generated to analyse Drebrin stability, localization and phosphorylation as well as analysing the effect of Drebrin overexpression on the nematodes’ vitality and fitness. The third project combined both generated models to obtain a genetic cross expressing Aβ(1-42) and Drebrin simultaneously. This model was sought to study the interaction between Aβ(1-42) and Drebrin. I could show, that Aβ(1-42) aggregates with the progression of ageing and exhibits multiple disease phenotypes that can be correlated to observations obtained in murine neurons as well as observations of AD patients’ brain tissues. Furthermore, I observed, that a distinct subset of head neurons of the anterior ganglion, the IL2 neurons, exhibits the first aggregates and that a cell-type specific suppression of Aβ(1-42) in IL2 neurons could delay the disease onset. Drebrin was observed to be regulated by phosphorylation at Serine-647 by Ataxia telangiectasia mutated kinase and render nematodes more resistant towards chronic oxidative stress. The genetic cross of Aβ(1-42) and Drebrin unravelled that overexpression of Drebrin can ameliorate Aβ(1-42) aggregation and toxicity and that this beneficial effect is dependent on phosphorylation of Drebrin-S647.
