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Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity

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An Erratum to this article was published on 20 December 2014

Abstract

The key role of APP in the pathogenesis of Alzheimer disease is well established. However, postnatal lethality of double knockout mice has so far precluded the analysis of the physiological functions of APP and the APLPs in the brain. Previously, APP family proteins have been implicated in synaptic adhesion, and analysis of the neuromuscular junction of constitutive APP/APLP2 mutant mice showed deficits in synaptic morphology and neuromuscular transmission. Here, we generated animals with a conditional APP/APLP2 double knockout (cDKO) in excitatory forebrain neurons using NexCre mice. Electrophysiological recordings of adult NexCre cDKOs indicated a strong synaptic phenotype with pronounced deficits in the induction and maintenance of hippocampal LTP and impairments in paired pulse facilitation, indicating a possible presynaptic deficit. These deficits were also reflected in impairments in nesting behavior and hippocampus-dependent learning and memory tasks, including deficits in Morris water maze and radial maze performance. Moreover, while no gross alterations of brain morphology were detectable in NexCre cDKO mice, quantitative analysis of adult hippocampal CA1 neurons revealed prominent reductions in total neurite length, dendritic branching, reduced spine density and reduced spine head volume. Strikingly, the impairment of LTP could be selectively rescued by acute application of exogenous recombinant APPsα, but not APPsβ, indicating a crucial role for APPsα to support synaptic plasticity of mature hippocampal synapses on a rapid time scale. Collectively, our analysis reveals an essential role of APP family proteins in excitatory principal neurons for mediating normal dendritic architecture, spine density and morphology, synaptic plasticity and cognition.

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Acknowledgments

We are grateful to Julia Gobbert, Michael Neumann, Claudia Meyer and Inger Drescher for excellent technical assistance. We thank Paul Mathews for kindly providing the M3.2 antibody and Klaus-Armin Nave for providing NexCre mice. We would also like to thank the Nikon Imaging Center (University of Heidelberg) for support with confocal microscopy and image analysis. This work was supported by the Deutsche Forschungsgemeinschaft Grants (MU 1457/8-1 and MU 1457/9-1, 9-2 to UM; KO 1674/3-1, 3-2 to MK; DR 326/7-1, 7-2 to AD), the ERA-Net Neuron (01EW1305A to UM) and the Breuer Stiftung (to UM). DPW is a member of the Zurich Center of Integrative Human Physiology ZIHP and the Neuroscience Center Zürich.

Conflict of interest

The authors declare no competing financial interests.

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Author notes

  1. Jan-Philipp Mallm

    Present address: Bioquant, Heidelberg University, Research Group Genome Organization & Function, Heidelberg, Germany

  2. Jakob-Andreas Tschäpe

    Present address: Roche Diagnostics International, Rotkreuz, Switzerland

Authors and Affiliations

  1. Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany

    Meike Hick, Sascha W. Weyer, Jan-Philipp Mallm, Jakob-Andreas Tschäpe & Ulrike C. Müller

  2. Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany

    Ulrike Herrmann & Martin Korte

  3. Neuroscience Therapeutic Area, Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Marianne Borgers & Marc Mercken

  4. Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

    Fabian C. Roth & Andreas Draguhn

  5. Institute of Anatomy, University of Zurich, Zurich, Switzerland

    Lutz Slomianka & David P. Wolfer

  6. Institute of Human Movement Sciences and Sport, ETH Zurich, Zurich, Switzerland

    David P. Wolfer

  7. AG NIND, HZI, Braunschweig, Germany

    Martin Korte

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Correspondence to Ulrike C. Müller.

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M. Hick and U. Herrmann have equal contribution.

M. Korte and U. C. Müller shared senior authorship.

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Hick, M., Herrmann, U., Weyer, S.W. et al. Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity. Acta Neuropathol 129, 21–37 (2015). https://doi.org/10.1007/s00401-014-1368-x

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  • DOI: https://doi.org/10.1007/s00401-014-1368-x

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