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Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer’s disease mouse model

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Abstract

Alzheimer’s disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions. It is commonly assumed that these deficits arise due to β-amyloid accumulation and plaque deposition. However, increasing evidence indicates that loss of physiological APP functions mediated predominantly by neurotrophic APPsα produced in the non-amyloidogenic α-secretase pathway may contribute to AD pathogenesis. Upregulation of APPsα production via induction of α-secretase might, however, be problematic as this may also affect substrates implicated in tumorigenesis. Here, we used a gene therapy approach to directly overexpress APPsα in the brain using AAV-mediated gene transfer and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1∆E9 AD model mice. Sustained APPsα overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and partially rescued spine density deficits. Importantly, AAV-APPsα treatment also resulted in a functional rescue of spatial reference memory in the Morris water maze. Moreover, we demonstrate a significant reduction of soluble Aβ species and plaque load. In addition, APPsα induced the recruitment of microglia with a ramified morphology into the vicinity of plaques and upregulated IDE and TREM2 expression suggesting enhanced plaque clearance. Collectively, these data indicate that APPsα can mitigate synaptic and cognitive deficits, despite established pathology. Increasing APPsα may therefore be of therapeutic relevance for AD.

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft Grants (MU 1457/9-1, 9-2 to UCM; KO 1674/3-1, 3-2 to MK), the ERA-Net Neuron (01EW1305A to CJB, NC and UCM), and the LOEWE Center for Cell and Gene Therapy Frankfurt funded by Hessisches Ministerium für Wissenschaft und Kunst (III L 4- 518/17.004 (2010)) to CJB.

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Authors and Affiliations

  1. INSERM U1169/MIRCen CEA, 92265, Fontenay aux Roses, France

    Romain Fol, Jerome Braudeau, Mickael Audrain & Nathalie Cartier

  2. University Paris Sud, University Paris-Saclay, 91400, Orsay, France

    Romain Fol, Jerome Braudeau, Mickael Audrain, Alexis-Pierre Bemelmans & Nathalie Cartier

  3. Université Paris Descartes, 75006, Paris, France

    Romain Fol & Mickael Audrain

  4. Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d’Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), 92260, Fontenay aux Roses, France

    Alexis-Pierre Bemelmans

  5. Centre National de la Recherche Scientifique (CNRS), UMR 9199, Neurodegenerative Diseases Laboratory, 92260, Fontenay aux Roses, France

    Alexis-Pierre Bemelmans

  6. Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225, Langen, Germany

    Tobias Abel, Florian Brod & Christian J. Buchholz

  7. Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Brunswick, Germany

    Susann Ludewig & Martin Korte

  8. Helmholtz Centre for Infection Research, AG NIND, Inhoffenstr. 7, 38124, Brunswick, Germany

    Martin Korte

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

    Sascha W. Weyer, Jan-Peter Roederer & Ulrike C. Müller

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  1. Romain Fol
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Corresponding authors

Correspondence to Nathalie Cartier or Ulrike C. Müller.

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The authors declare no conflict of interest.

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R. Fol and J. Braudeau are joint first authors.

N. Cartier and U. C. Müller are joint senior authors.

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Fol, R., Braudeau, J., Ludewig, S. et al. Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer’s disease mouse model. Acta Neuropathol 131, 247–266 (2016). https://doi.org/10.1007/s00401-015-1498-9

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  • DOI: https://doi.org/10.1007/s00401-015-1498-9

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