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Development and characterization of a Drosophila Alzheimer model
Abstract   Open access   Peer reviewed

Development and characterization of a Drosophila Alzheimer model

Aleister J. Saunders, Daniel R. Marenda, Ranjita Chakraborty and Vidya Vepuri
Alzheimer's & dementia, v 6(4S Part 8), pp S227-S227
Jul 2010
DOI: https://doi.org/10.1016/j.jalz.2010.05.733
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https://doi.org/10.1016/j.jalz.2010.05.733View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Background A central event in Alzheimer's disease (AD) is the sequential cleavage of the β-amyloid precursor protein (APP) by β-and γ-secretase enzymes generating the amyloid-beta (Aβ) peptide. Aggregation of Aβ is a major pathological hallmark of AD. It is important to identify regulators of APP processing and Aβ production for developing any therapeutic intervention. Developing in vivo disease models has proven crucial to illuminating disease mechanisms, since in vitro studies don't always represent the natural physiology of the tissue and/or organism. Here we have developed and characterized a Drosophila model of AD that allows the natural processing of APP by β- and γ-secretase in the central nervous system (CNS) to produce Aβ peptides. Methods Human APP and BACE were expressed in the central nervous system of Drosophila using ELAV-Gal4 driver. Flies were raised at 25C on normal media in the presence or absence of pharmacologic agents. Longevity, learning and memory, as well as reflexive motor function, were measured. CNS pathology were analyzed using confocal microscropy with aid of antibodies and Thioflavin S. Results We show here that our AD model flies have reduced longevity, abnormal exterior morphology, and defective reflexive motor function. These flies also display impaired immediate recall memory but normal learning. The brain structures associated with learning and memory are significantly decreased in size compared to control flies. Amyloid plaques are readily observed in disease model brains. Each of these disease model associated neuroanatomical and behavioral defects can be rescued with treatment with a the γ-secretase inhibitor, L-685,458. To validate the disease model we treated AD flies with the Sir2/SirT1 agonist reseveratrol, which has been shown to decrease AD-pathology in neurons and AD transgenic mice. Resveratrol treatment significantly improves longevity, neuroanatomical and behavioral phenotypes of the AD flies. Given this success we now turn to utilizing this model to identify and characterize novel regulators of APP metabolism. Conclusions We have developed and characterized a new AD model in Drosophila. This model recapitulates the neuroanatomical and behavioral aspects of the disease and we plan to use it to identify novel therapeutic strategies and therapeutic targets.

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