title: Expression of human amyloid precursor protein in the skeletal muscles of Drosophila results in age- and activity-dependent muscle weakness.
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.
authors.affiliation: Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Chul
authors.initials: C
authors.lastname: Kim
authors.forename: Sapeckshita
authors.initials: S
authors.lastname: Srivastava
authors.forename: Marian
authors.initials: M
authors.lastname: Rice
authors.forename: Tanja A
authors.initials: TA
authors.lastname: Godenschwege
authors.forename: Brooke
authors.initials: B
authors.lastname: Bentley
authors.forename: Saranya
authors.initials: S
authors.lastname: Ravi
authors.forename: Shuang
authors.initials: S
authors.lastname: Shao
authors.forename: Craig T
authors.initials: CT
authors.lastname: Woodard
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Schwartz
mesh_terms: D000375:Aging; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000502:physiology*; D015444:Exercise; D005426:Flight, Animal; D017952:Ganglia, Invertebrate / Q000503:physiopathology; D005898:Glass; D006799:Housing, Animal; D006801:Humans; D007763:Lac Operon; D009046:Motor Neurons / Q000502:physiology; D018908:Muscle Weakness / Q000209:etiology*; D009132:Muscles / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000503:physiopathology*; D010969:Plastics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D019076:Transgenes
chemical_list: D016564:Amyloid beta-Protein Precursor; D010969:Plastics; D011993:Recombinant Fusion Proteins