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Open Access Research article

Expression of human amyloid precursor protein in the skeletal muscles of Drosophila results in age- and activity-dependent muscle weakness

Chul Kim1, Sapeckshita Srivastava2, Marian Rice3, Tanja A Godenschwege4, Brooke Bentley5, Saranya Ravi3, Shuang Shao3, Craig T Woodard3 and Lawrence M Schwartz125*

Author Affiliations

1 Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA 01003, USA

2 Department of Biology, University of Massachusetts, Amherst, MA 01003, USA

3 Department of Biological Sciences, Mount Holyoke College, South Hadley, MA 01075, USA

4 Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA

5 Pioneer Valley Life Sciences Institute, 3601 Main Street, Springfield, MA, 01199, USA

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BMC Physiology 2011, 11:7  doi:10.1186/1472-6793-11-7

Published: 25 April 2011

Abstract

Background

One of the hallmarks of Alzheimer's disease, and several other degenerative disorders such as Inclusion Body Myositis, is the abnormal accumulation of amyloid precursor protein (APP) and its proteolytic amyloid peptides. To better understand the pathological consequences of inappropriate APP expression on developing tissues, we generated transgenic flies that express wild-type human APP in the skeletal muscles, and then performed anatomical, electrophysiological, and behavioral analysis of the adults.

Results

We observed that neither muscle development nor animal longevity was compromised in these transgenic animals. However, human APP expressing adults developed age-dependent defects in both climbing and flying. We could advance or retard the onset of symptoms by rearing animals in vials with different surface properties, suggesting that human APP expression-mediated behavioral defects are influenced by muscle activity. Muscles from transgenic animals did not display protein aggregates or structural abnormalities at the light or transmission electron microscopic levels. In agreement with genetic studies performed with developing mammalian myoblasts, we observed that co-expression of the ubiquitin E3 ligase Parkin could ameliorate human APP-induced defects.

Conclusions

These data suggest that: 1) ectopic expression of human APP in fruit flies leads to age- and activity-dependent behavioral defects without overt changes to muscle development or structure; 2) environmental influences can greatly alter the phenotypic consequences of human APP toxicity; and 3) genetic modifiers of APP-induced pathology can be identified and analyzed in this model.

Keywords:
amyloid precursor protein (APP); Drosophila; muscle; mitochondria; electron microscopy; apoptosis; Parkin