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

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.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.Amyloid precursor protein (APP) is a type I glycotransmembrane protein with a large extracellular domain and a short cytoplasmic tail [reviewed in 1]. Its role in normal biological processes is poorly defined, but there is mounting evidence that it plays both autocrine and endocrine roles in neurite growth and enhanced memory function in mice [2,3].APP became the subject of intense investigation when it was identified as a risk factor for Alzheimer's disease (AD) [4]. Individuals with an extra copy of the APP gene due to trisomy of chromosome 21 (Down Syndrome) also display early onset AD [5]. One point mutation in APP, referred to as the Swedish mutation, results in an early onset familial AD [6].APP can be subjected to combinatorial cleavage by three different intramembrane secretases (α, β, and γ) to create a number of smaller peptides [7]. C