Experimental Brain Research

, Volume 217, Issue 3–4, pp 353–364 | Cite as

Axonal transport of APP and the spatial regulation of APP cleavage and function in neuronal cells

  • Silke Brunholz
  • Sangram Sisodia
  • Alfredo Lorenzo
  • Carole Deyts
  • Stefan Kins
  • Gerardo Morfini
Review

Abstract

Over two decades have passed since the original discovery of amyloid precursor protein (APP). While physiological function(s) of APP still remain a matter of debate, consensus exists that the proteolytic processing of this protein represents a critical event in the life of neurons and that abnormalities in this process are instrumental in Alzheimer’s disease (AD) pathogenesis. Specific molecular components involved in APP proteolysis have been identified, and their enzymatic activities characterized in great detail. As specific proteolytic fragments of APP are identified and novel physiological effects for these fragments are revealed, more obvious becomes our need to understand the spatial organization of APP proteolysis. Valuable insights on this process have been obtained through the study of non-neuronal cells. However, much less is known about the topology of APP processing in neuronal cells, which are characterized by their remarkably complex cellular architecture and extreme degree of polarization. In this review, we discuss published literature addressing various molecular mechanisms and components involved in the trafficking and subcellular distribution of APP and APP secretases in neurons. These include the relevant machinery involved in their sorting, the identity of membranous organelles in which APP is transported, and the molecular motor-based mechanisms involved in their translocation. We also review experimental evidence specifically addressing the processing of APP at the axonal compartment. Understanding neuron-specific mechanisms of APP processing would help illuminating the physiological roles of APP-derived proteolytic fragments and provide novel insights on AD pathogenesis.

Keywords

Alzheimer’s disease Amyloid precursor protein Secretases Kinesin Axonal transport 

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Silke Brunholz
    • 1
  • Sangram Sisodia
    • 2
  • Alfredo Lorenzo
    • 3
  • Carole Deyts
    • 4
  • Stefan Kins
    • 1
  • Gerardo Morfini
    • 5
  1. 1.Department of Human Biology and Human GeneticsTechnical University of KaiserslauternKaiserslauternGermany
  2. 2.Department of Neurobiology, Pharmacology and Physiology, Center for Molecular NeurobiologyThe University of ChicagoChicagoUSA
  3. 3.Instituto de Investigación Médica Mercedes y Martín Ferreyra (INIMEC-CONICET) y Departamento de Farmacología, Facultad de Ciencias QuímicasUniversidad Nacional de CórdobaCordobaArgentina
  4. 4.Department of NeurobiologyUniversity of ChicagoChicagoUSA
  5. 5.Department of Anatomy and Cell Biology MC512University of Illinois at ChicagoChicagoUSA

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