期刊
NEUROBIOLOGY OF AGING
卷 30, 期 2, 页码 241-256出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2007.06.011
关键词
NMDA-receptor; Oligomeric; Amyloid peptides; APP transgenic mice; Synaptic plasticity; c-Fos
资金
- DFG
- Bayerische Forschungsverbunt ForPrion
- Polish MNSW Scientific Network
- UE [QLRT-2001-02775]
- Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO-Vlaanderen)
- Instituut voor Wetenschappelijk en Technologisch onderzoek (IWT)
- EEC-6th Framework Program
- Rooms-fund
- K.U.Leuven Special Research
- K.U.Leuven-RD
- FWO-Vlaanderen
- NFSR
- Queen Elisabeth Fund for Medical Research
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 oil 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 ill 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 finding,, 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. (C) 2007 Elsevier Inc. All rights reserved.
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