Abstract
Alzheimer’s disease is a widespread and devastating neurological disorder associated with proteotoxic events caused by the misfolding and aggregation of the amyloid-β peptide. To find therapeutic strategies to combat this disease, Drosophila melanogaster has proved to be an excellent model organism that is able to uncover anti-proteotoxic candidates due to its outstanding genetic toolbox and resemblance to human disease genes. In this review, we highlight the use of Drosophila melanogaster to both study the proteotoxicity of the amyloid-β peptide and to screen for drug candidates. Expanding the knowledge of how the etiology of Alzheimer’s disease is related to proteotoxicity and how drugs can be used to block disease progression will hopefully shed further light on the field in the search for disease-modifying treatments.
Highlights
Neurodegenerative diseases, such as Alzheimer’s disease (AD), are associated with proteotoxicity, which is caused by protein aggregation and results in extensive neuronal damage in the brain
The following year, a similar model of Aβ1-42 proteotoxicity was published where the peptide was again expressed in the neurons using the Gal4/upstream activating sequence (UAS) system, but, in this model, a signal peptide was connected to Aβ1-42 to allow for secretion [15]
Since different isoforms of the Aβ peptide can be found in the AD brain, it is important to consider their possible triggering effect on each other, causing a seeding cascade followed by proteotoxicity
Summary
Neurodegenerative diseases, such as Alzheimer’s disease (AD), are associated with proteotoxicity, which is caused by protein aggregation and results in extensive neuronal damage in the brain. Drosophila offers a number of advantages as a model system for studying diseases where: (i) a variety of phenotypic markers are available for identifying detrimental effects due to proteotoxicity, (ii) the lifespan of Drosophila makes it possible to investigate age-related diseases on a reasonable time scale (days to weeks, as opposed to months and years, in mouse model systems), (iii) the system is amenable to large drug screens since the flies proliferate well and are relatively inexpensive and easy to work with and (vi) there are extensive tools that allow disease-related genes and molecular pathways to be genetically and pharmacologically manipulated in order to find out both the function of their orthologs in vivo, and how these genes are involved in the pathogenesis of different diseases, which can generate in vivo data that are translatable to mammalian system [6,7].
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