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Expression of mDab1 promotes the stability and processing of amyloid precursor protein and this effect is

Loukia Parisiadou1, Spiros Efthimiopoulos

  • 1Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, 157 84 Panepistimiopolis, Ilisia, Athens, Greece.

Neurobiology of Aging
|February 7, 2006
PubMed

Insights

The adaptor protein mDab1 promotes amyloid precursor protein (APP) processing and cell surface expression. Its effects are dependent on the NPTY motif, opposing X11alpha

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • The amyloid precursor protein (APP) cytoplasmic tail contains the NPTY motif, a binding site for phosphotyrosine-binding domain proteins like X11alpha and mDab1.
  • X11alpha binding to APP inhibits APP processing and reduces amyloid-beta (Abeta) peptide secretion.
  • The impact of mDab1 on APP processing remains largely uncharacterized.

Purpose of the Study:

  • To investigate the role of mDab1 in amyloid precursor protein (APP) processing and cellular localization.
  • To compare the effects of mDab1 and X11alpha on APP metabolism.
  • To elucidate how the interaction between APP and adaptor proteins influences APP processing.

Main Methods:

  • Transient transfection of HEK 293 and neuroglioma U251 cells with APP and mDab1 constructs.
  • Analysis of mature APP levels and secretase-mediated processing.
  • Assessment of cell surface APP expression using APP deletion mutants lacking the NPTY motif.
  • Co-expression studies of APP with X11alpha and mDab1.

Main Results:

  • mDab1 significantly increases mature APP levels and enhances its processing by secretases in transfected cells.
  • These effects are contingent upon the direct interaction between APP and mDab1 via the NPTY motif.
  • mDab1 promotes cell surface expression of APP, potentially by inhibiting endocytosis.
  • mDab1 and X11alpha exhibit opposing effects on APP processing, with X11alpha's influence dominating upon co-expression.

Conclusions:

  • mDab1 modulates APP processing and cell surface levels through its interaction with the APP NPTY motif.
  • The opposing actions of mDab1 and X11alpha highlight the complex regulation of APP metabolism.
  • The net outcome of APP processing is determined by the relative stoichiometry and binding affinities of interacting adaptor proteins.

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