Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult

Shaefali P. Rodgers, Heather A. Born, Pritam Das, Joanna L. Jankowsky

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background: Transgenic mice expressing disease-associated proteins have become standard tools for studying human neurological disorders. Transgenes are often expressed using promoters chosen to drive continuous highlevel expression throughout life rather than temporal and spatial fidelity to the endogenous gene. This approach has allowed us to recapitulate diseases of aging within the two-year lifespan of the laboratory mouse, but has the potential for creating aberrant phenotypes by mechanisms unrelated to the human disorder. Results: We show that overexpression of the Alzheimer's-related amyloid precursor protein (APP) during early postnatal development leads to severe locomotor hyperactivity that can be significantly attenuated by delaying transgene onset until adulthood. Our data suggest that exposure to transgenic APP during maturation influences the development of neuronal circuits controlling motor activity. Both when matched for total duration of APP overexpression and when matched for cortical amyloid burden, animals exposed to transgenic APP as juveniles are more active in locomotor assays than animals in which APP overexpression was delayed until adulthood. In contrast to motor activity, the age of APP onset had no effect on thigmotaxis in the open field as a rough measure of anxiety, suggesting that the interaction between APP overexpression and brain development is not unilateral. Conclusions: Our findings indicate that locomotor hyperactivity displayed by the tet-off APP transgenic mice and several other transgenic models of Alzheimer's disease may result from overexpression of mutant APP during postnatal brain development. Our results serve as a reminder of the potential for unexpected interactions between foreign transgenes and brain development to cause long-lasting effects on neuronal function in the adult. The tetoff APP model provides an easy means of avoiding developmental confounds by allowing transgene expression to be delayed until the mice reach adulthood.

Original languageEnglish (US)
Article number28
JournalMolecular Neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - 2012

Fingerprint

Amyloid beta-Protein Precursor
Transgenes
Amyloid
Transgenic Mice
Brain
Motor Activity
Mutant Proteins
Nervous System Diseases
Alzheimer Disease
Anxiety
Phenotype

Keywords

  • Alzheimers disease
  • Amyloid precursor protein
  • Amyloid-
  • APP
  • Motor hyperactivity
  • neurodevelopment
  • Tet-off
  • Tetracycline-controllable
  • Transgenic mouse

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult. / Rodgers, Shaefali P.; Born, Heather A.; Das, Pritam; Jankowsky, Joanna L.

In: Molecular Neurodegeneration, Vol. 7, No. 1, 28, 2012.

Research output: Contribution to journalArticle

Rodgers, Shaefali P. ; Born, Heather A. ; Das, Pritam ; Jankowsky, Joanna L. / Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult. In: Molecular Neurodegeneration. 2012 ; Vol. 7, No. 1.
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