From synaptic spines to nuclear signaling: nuclear and synaptic actions of the amyloid precursor protein

Authors

  • Jean-Noël Octave,

    Corresponding author
    • Université Catholique de Louvain, Institute of Neuroscience (IoNS), Brussels, Belgium
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  • Nathalie Pierrot,

    1. Université Catholique de Louvain, Institute of Neuroscience (IoNS), Brussels, Belgium
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  • Susana Ferao Santos,

    1. Université Catholique de Louvain, Institute of Neuroscience (IoNS), Brussels, Belgium
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  • Natalia N. Nalivaeva,

    1. School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
    2. I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, RAS, St. Petersburg, Russia
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  • Anthony J. Turner

    Corresponding author
    1. School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
    • Université Catholique de Louvain, Institute of Neuroscience (IoNS), Brussels, Belgium
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Address correspondence and reprint requests to Jean-Noël Octave, Universite catholique de Louvain, Institute of Neuroscience (IoNS), Avenue Hippocrate 53, IONS/5306, B-1200 Brussels, Belgium. E-mail: jean-noel.octave@uclouvain.be or Anthony J. Turner, School of Molecular and Cellular Biology,Faculty of Biological Sciences,University of Leeds, Leeds LS2 9JT, UK. E-mail: a.j.turner@leeds.ac.uk

Abstract

Despite intensive studies of the secretase-mediated processing of the amyloid precursor protein (APP) to form the amyloid β-peptide (Aβ), in relation to Alzheimer's disease (AD), no new therapeutic agents have reached the clinics based on reducing Aβ levels through the use of secretase inhibitors or immunotherapy. Furthermore, the normal neuronal functions of APP and its various metabolites still remain under-investigated and unclear. Here, we highlight emerging areas of APP function that may provide new insights into synaptic development, cognition, and gene regulation. By modulating expression levels of endogenous APP in primary cortical neurons, the frequency and amplitude of calcium oscillations is modified, implying a key role for APP in maintaining neuronal calcium homeostasis essential for synaptic transmission. Disruption of this homeostatic mechanism predisposes to aging and AD. Synaptic spine loss is a feature of neurogeneration resulting in learning and memory deficits, and emerging evidence indicates a role for APP, probably mediated via one or more of its metabolites, in spine structure and functions. The intracellular domain of APP (AICD) has also emerged as a key epigenetic regulator of gene expression controlling a diverse range of genes, including APP itself, the amyloid-degrading enzyme neprilysin, and aquaporin-1. A fuller understanding of the physiological and pathological actions of APP and its metabolic network could provide new opportunities for therapeutic intervention in AD.

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