Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice

Kemppainen, Susanna; Rantamäki, Tomi; Jerónimo-Santos, André; Lavasseur, Gregoire; Autio, Henri; Karpova, Nina; Kärkkäinen, Elisa; Stavén, Saara; Miranda, Hugo Vicente; Outeiro, Tiago F.; Diógenes, Maria J.; Laroche, Serge; Davis, Sabrina; Sebastião, Ana M.; Castrén, Eero; Tanila, Heikki

doi:10.1016/j.neurobiolaging.2011.11.006

« Previous Next »Neurobiology of Aging
Volume 33, Issue 6 , Pages 1122.e23-1122.e39, June 2012

Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice

Susanna Kemppainen
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
Tomi Rantamäki
- Neuroscience Center, University of Helsinki, Helsinki, Finland
André Jerónimo-Santos
- Institute of Pharmacology and Neurosciences, Faculty of Medicine and Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
Gregoire Lavasseur
- CNRS, UMR 8195, Orsay, France
- Univ Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, France
Henri Autio
- Neuroscience Center, University of Helsinki, Helsinki, Finland
Nina Karpova
- Neuroscience Center, University of Helsinki, Helsinki, Finland
Elisa Kärkkäinen
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
Saara Stavén
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
Hugo Vicente Miranda
- Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisboa, Portugal
Tiago F. Outeiro
- Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisboa, Portugal
- Instituto de Fisiologia, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
- Department of NeuroDegeneration and Restaurative Research, University Medizin Gottingen, Gottingen, Germany
Maria J. Diógenes
- Institute of Pharmacology and Neurosciences, Faculty of Medicine and Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
Serge Laroche
- CNRS, UMR 8195, Orsay, France
- Univ Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, France
Sabrina Davis
- CNRS, UMR 8195, Orsay, France
- Univ Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, France
Ana M. Sebastião
- Institute of Pharmacology and Neurosciences, Faculty of Medicine and Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
Eero Castrén
- Neuroscience Center, University of Helsinki, Helsinki, Finland
Heikki Tanila
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
- Neuroscience Center, University of Helsinki, Helsinki, Finland
- Department of Neurology, Kuopio University Hospital, Kuopio, Finland
- Corresponding author at: A. I. Virtanen Institute, University of Eastern Finland, P.O. Box 1627, Neulaniementie 2, 70211 Kuopio, Finland. Tel.: +358-40-3552084; fax: +358-17-163030

Received 19 July 2011; received in revised form 25 October 2011; accepted 4 November 2011. published online 03 January 2012.

Abstract

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory. Levels of BDNF and its main receptor TrkB (TrkB.TK) have been reported to be decreased while the levels of the truncated TrkB (TrkB.T1) are increased in Alzheimer's disease. We show here that incubation with amyloid-β increased TrkB.T1 receptor levels and decreased TrkB.TK levels in primary neurons. In vivo, APPswe/PS1dE9 transgenic mice (APdE9) showed an age-dependent relative increase in cortical but not hippocampal TrkB.T1 receptor levels compared with TrkB.TK. To investigate the role of TrkB isoforms in Alzheimer's disease, we crossed AP mice with mice overexpressing the truncated TrkB.T1 receptor (T1) or the full-length TrkB.TK isoform. Overexpression of TrkB.T1 in APdE9 mice exacerbated their spatial memory impairment while the overexpression of TrkB.TK alleviated it. These data suggest that amyloid-β changes the ratio between TrkB isoforms in favor of the dominant-negative TrkB.T1 isoform both in vitro and in vivo and supports the role of BDNF signaling through TrkB in the pathophysiology and cognitive deficits of Alzheimer's disease.

Keywords: BDNF , Tyrosine kinase receptor , Amyloid , Memory , Hyperactivity