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Experimental Genetics Group
Neurobiol Aging. 2009 Feb;30(2):241-56. Dewachter I1*, Filipkowski RK2*, Priller C3*, Ris L5, Neyton J4, Croes S1, Terwel D1, Gysemans M6, Devijver H1, Borghgraef P1, Godaux E5, Kaczmarek L2, Herms J3, Van Leuven F1**. 1Experimental Genetics Group, LEGT_EGG, K.U.Leuven, Leuven, Belgium. 2Laboratory of Molecular Neurobiology, Nencki Institute, Warsawa, Poland. 3Department of Neuropathology, Ludwig-Maximilians-Universität Muenich, Muenich, Germany. 4Laboratoire de Neurobiologie, CNRS UMR 8544 Ecole Normale Superieure, Paris, France. 5Université de Mons-Hainaut, Faculté de Medecine et Pharmacie, Mons, Belgium. 6Laboratory of Solid State Physics and Magnetism, K.U.Leuven, Leuven, Belgium. *These authors contributed equally to this work. **Corresponding author. Evidence is accumulating for a role for amyloid peptides in impaired synaptic plasticity and cognition, while the underlying mechanisms remain unclear. We here analyzed the effects of amyloid peptides on NMDA-receptor function in vitro and in vivo. A synthetic amyloid peptide preparation containing monomeric and oligomeric A beta (1-42) peptides was used and demonstrated to bind to synapses expressing NMDA-receptors in cultured hippocampal and cortical neurons. Pre-incubation of primary neuronal cultures with A beta peptides significantly inhibited NMDA-receptor function, albeit not by a direct pharmacological inhibition of NMDA-receptors, since acute application of A beta peptides did not change NMDA-receptor currents in autaptic hippocampal cultures nor in xenopus oocytes expressing recombinant NMDA-receptors. Pre-incubation of primary neuronal cultures with A beta peptides however decreased NR2B-immunoreactive synaptic spines and surface expression of NR2B containing NMDA-receptors. Furthermore, we extended these findings for the first time in vivo, demonstrating decreased concentrations of NMDA-receptor subunit NR2B and PSD-95 as well as activated alpha-CaMKII in postsynaptic density preparations of APP[V717I] transgenic mice. This was associated with impaired NMDA-dependent LTP and decreased NMDA- and AMPA-receptor currents in hippocampal CA1 region in APP[V717I] transgenic mice. In addition, induction of c-Fos following cued and contextual fear conditioning was significantly impaired in the basolateral amygdala and hippocampus of APP[V717I] transgenic mice. Our data demonstrate defects in NMDA-receptor function and learning dependent signaling cascades in vivo in APP[V717I] transgenic mice and point to decreased surface expression of NMDA-receptors as a mechanism involved in early synaptic defects in APP[V717I] transgenic mice in vivo.  FULL TEXT |
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