In-vivo-Screen verschiedener Aggregationsmodulatoren in transgenen Drosophila melanogaster Alzheimermodellen

In-vivo-screen of different modulators of aggregation in transgenic Drosophila melanogaster models of Alzheimer's disease

by Petra Maria Theodora Bernharda Wilken
Doctoral thesis
Date of Examination:2016-12-15
Date of issue:2017-01-27
Advisor:PD Dr. Anja Schneider
Referee:PD Dr. Oliver Wirths
Referee:Prof. Dr. Markus Zweckstetter
Persistent Address: http://dx.doi.org/10.53846/goediss-6030

 

 

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Abstract

English

This study was aimed at evaluating different modulators of amyloid-beta aggregation in Drosophila melanogaster models of Alzheimer’s disease. Fly model studies are cost-effective and fast in vivo systems to screen therapeutic compounds for further testing in mouse models. Oligomers are described to be the key neurotoxic agents in neurodegenerative diseases such as Alzheimer’s disease. Previously it has been shown that anle138b, a di-phenyl-pyrazol, inhibits aggregation of prion protein and α-synuclein. We used flies expressing the arctic mutant (Glu22Gly) of amyloid beta 42 fused to a secretion signal to allow extracellular aggregation. As readout of amyloid-mediated toxicity we first expressed amyloid beta arctic in photoreceptor cells, using the UAS Gal4 System and assessed eye morphology of flies either treated with different aggregation inhibitors or solvent control. This approach captures developmental effects of amyloid beta toxicity rather than degeneration. Therefore we switched to a heat inducible expression system which allows start of expression under the neuronal elav promotor directly after hatching (elavGal4arc2e;tubGal80). We examined the influence of nine different inhibitors of aggregation on longevity compared to solvent control. The administration of the inhibitors anle138b and anle138c in the Drosophila model elavGal4/arc2e;tubGal80 showed a significantly prolonged mean survival time in contrast to the control group treated with DMSO alone. Importantly, survival of lacZ overexpression controls was not prolonged, thus excluding an unspecific effect of these compounds on the life-span.
Keywords: anle138b; dementia; Drosophila melanogaster; anle138c; oligomer; aggregation inhibitors; eye morphology; longevity; Alzheimer´s disease
Schlagwörter: Alzheimer; Drosophila melanogaster; anle138b; Demenz; anle138c; Oligomere; Aggregations Hemmstoffe; Augenphänotyp; Lebensdauer
 
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