Rogers, I.; (2012) Development, characterisation and application of an inducible model of Alzheimer’s Disease in the fruit fly, Drosophila melanogaster. Doctoral thesis , UCL (University College London).

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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the most prevalent form of senile dementia, affecting more than 26 million people worldwide. The amyloid-β42 peptide (Aβ42) has been suggested to play a central role in the pathogenesis of AD. Although the primary etiologic mechanism of AD is unknown, it has a clear association with age. However, is it ageing, the slow erosion of biological function, that is the cause of AD; or is ageing merely a measure of how long it takes to accumulate toxic levels of Aβ? To distinguish between age-dependent and age-independent effects on the rate and extent of AD pathogenesis, an inducible model of Aβ toxicity was developed in the fruit fly Drosophila melanogaster. This is a model system where expression of Aβ peptides can be induced for the first time, or turned off, at different ages. Induced expression of the human Arctic mutant Aβ42 peptide in Drosophila neural tissue resulted in flies with age-dependent locomotor and electrophysiology deficits and shortened lifespan. Conditional expression of Arctic Aβ42 at different ages was then used to show that ageing renders flies more vulnerable to Aβ42 toxicity. The results of this thesis also served to highlight the technical drawbacks of the GeneSwitch system and the complexities of measuring the effect of ageing interventions such as reduced insulin signalling and the drug rapamycin on Aβ toxicity in Drosophila.

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