Characterization of a Drosophila Alzheimer's Disease Model: Pharmacological Rescue of Cognitive Defects

Ranjita Chakraborty,Jeremy C Lee,Radha Delvadia,Aleister J Saunders,Siddhita D Mhatre,Marianna Vinokur,Vidya Vepuri,Sarah J Michelson,Robert D Moir,Daniel R Marenda,Sara Ansaloni,Suruchi Utreja,David J Melicharek,Sean Miller,Lee E Goldstein,Loni Philip Tabb ,A Desai ,Brie Paddock ,Preeti J Khandelwal

doi:10.1371/journal.pone.0020799

Abstract

Transgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of Aβ40 and Aβ42, the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a γ-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in the developed world [1]
This indicates that c-secretase activity is inhibited successfully in these flies, as is the subsequent production of Ab. This result was confirmed by Western blot analysis of elav; APP; BACE fly heads, which demonstrate decreased Ab levels in the L-685,458 treated flies compared to the DMSO raised elav; APP; BACE heterozygous flies (Figure S1C and S1F)
Consistent with this, we observed increased bCTF levels in the elav; APP; BACE heterozygous flies raised on L685,458 containing food compared to those raised on DMSO (Figures S1B and S1F), as well as a modest increase in full length APP levels in flies raised on L-685,458 (Figures S1A and S1F)

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in the developed world [1]. Several lines of evidence support the amyloid hypothesis of AD, according to which Ab plays the central role in initiating the AD pathogenic cascade [4]. Ab peptides are generated by proteolytic processing of the bamyloid precursor protein (APP) through sequential proteolysis by b- and c-secretases in the amyloidogenic processing pathways [5]. This pathway is initiated when APP undergoes proteolytic cleavage by b-secretase, encoded by the BACE gene. This cleavage produces a soluble extracellular/lumenal fragment of APP (sAPPb) and a membrane spanning C-terminal fragment (bCTF/C99). Compared to Ab40, Ab42 is more prone to oligomerization and has been shown to be more neurotoxic [6]

Methods

Results

Conclusion