Compound Screening In A Drosophila melanogaster Alzheimer's Disease Model Using A Behavioral Readout

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease affecting the elderly, absconding with their memory and cognitive function. It has been classically characterized by severe dementia associated with amyloid plaques and neurofibrillary tangles in the CNS. Currently, there are no drugs that effectively ameliorate or abate disease progression. Vitruvean, LLC has strived to develop a Drosophila melanogaster-based behavioral screening platform for rapid discovery and validation of treatments for neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington's diseases. Our system exploits the fly's innate negative geotaxis response and assesses changes in progressively degenerating climbing behavior as the flies ascend the vial walls. In this fully automated system, we demonstrate that we can improve behavior of models that overexpress derivatives of human APP and human tau transgenes in the Drosophila CNS with compound intervention. Kinase inhibitors and gamma secretase inhibitors have been shown to improve disease pathology while cholinesterase inhibitors have been shown to improve cognition. Members of these compound classes show positive effects in our disease models, both in behavioral improvement and in pathological attenuation. Furthermore, this screening system has the capacity to assess 1536 vials of flies dosed with differing compound treatments, and hence provides a mechanism for assessing a large number of drug candidates in a disease relevant, behavioral paradigm. Vitruvean hopes to use this behavioral screening system to identify novel, more effective treatments for Alzheimer's disease.