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

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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.

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Acknowledgments

This work was supported by NIH RO1 NS066942A, ALS/CVS Therapy Alliance and Brain Research Foundation grants to G.M.; grants form CONICET, SECyT-UNC, and ANPCyT06-01941 to A. L.; Cure Alzheimer’s Fund, Adler Foundation, and NIH RO1 AG021494 grants to S.S; and Deutsche Forschungsgemeinschaft FOR1332 (KI 819/5-1 and/6-1) grants to S. K. SS discloses that he is a paid Consultant of Noscira, Inc and Eisai Research Labs Inc, but is not a shareholder in any company that is a maker or owner of a FDA-regulated drug or device.

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Authors and Affiliations

  1. Department of Human Biology and Human Genetics, Technical University of Kaiserslautern, Kaiserslautern, Germany

    Silke Brunholz & Stefan Kins

  2. Department of Neurobiology, Pharmacology and Physiology, Center for Molecular Neurobiology, The University of Chicago, Chicago, IL, 60637, USA

    Sangram Sisodia

  3. Instituto de Investigación Médica Mercedes y Martín Ferreyra (INIMEC-CONICET) y Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Cordoba, Argentina

    Alfredo Lorenzo

  4. Department of Neurobiology, University of Chicago, Chicago, IL, 60637, USA

    Carole Deyts

  5. Department of Anatomy and Cell Biology MC512, University of Illinois at Chicago, 808 S Wood St Room 578, Chicago, IL, 60612, USA

    Gerardo Morfini

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  1. Silke Brunholz
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  2. Sangram Sisodia
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  3. Alfredo Lorenzo
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  4. Carole Deyts
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  5. Stefan Kins
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  6. Gerardo Morfini
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Correspondence to Gerardo Morfini.

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Brunholz, S., Sisodia, S., Lorenzo, A. et al. Axonal transport of APP and the spatial regulation of APP cleavage and function in neuronal cells. Exp Brain Res 217, 353–364 (2012). https://doi.org/10.1007/s00221-011-2870-1

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