Deregulation of NMDA-receptor function and down-stream signaling in APP[V717I] transgenic mice.
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.
Dewachter
I
I
Experimental Genetics Group, LEGT_EGG, K.U.Leuven, Campus Gasthuisberg ON1-06.602, 3000 Leuven, Belgium.
Filipkowski
R K
RK
Priller
C
C
Ris
L
L
Neyton
J
J
Croes
S
S
Terwel
D
D
Gysemans
M
M
Devijver
H
H
Borghgraef
P
P
Godaux
E
E
Kaczmarek
L
L
Herms
J
J
Van Leuven
F
F
D016229:Amyloid beta-Peptides / Q000008:administration & dosage*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage*; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42)