Journal
JOURNAL OF NEUROSCIENCE
Volume 24, Issue 13, Pages 3370-3378Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1633-03.2004
Keywords
amyloid beta-protein; LTP; metabotropic glutamate receptors; hippocampus; JNK; Cdk5; p38 MAPK; Alzheimer's disease
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Funding
- Wellcome Trust Funding Source: Medline
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The mechanisms of action of human synthetic and naturally secreted cell-derived amyloid beta-peptide (Abeta)(1-42) on the induction of long-term potentiation (LTP) were investigated in the medial perforant path to dentate granule cell synapses in hippocampal slices. Synthetic and cell-derived Abeta strongly inhibited high-frequency stimulation (HFS)-induced LTP at peak HFS and 1 hr after HFS. Cell-derived Abeta was much more potent than synthetic Abeta at inhibiting LTP induction, with threshold concentrations of similar to1 and 100-200 nM, respectively. The involvement of various kinases in Abeta-mediated inhibition of LTP induction was investigated by applying Abeta in the presence of inhibitors of these kinases. The c-Jun N-terminal kinase (JNK) inhibitor JNKI prevented the block of LTP induction by both synthetic and cell-derived Abeta. The block of LTP induced by synthetic Abeta was also prevented by the JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-one, the cyclin-dependent kinase 5 (Cdk5) inhibitors butyrolactone and roscovitine, and the p38 MAP kinase (MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole but not by the p42-p44 MAP kinase inhibitor 1,4-diamino2,3-dicyano-1,4-bis(2-inophenylthio)butadiene. The group I-group II metabotropic glutamate receptor (mGluR) antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid and the mGluR5 antagonist methyl-6-(phenylethynyl) pyridine prevented the block of LTP induction byAbeta. However, the alpha7 nicotinic ACh receptor antagonist methylcaconatine did not prevent the inhibition of LTP induction byAbeta. These studies provide evidence that theAbeta-mediated inhibition of LTP induction involves stimulation of the kinases JNK, Cdk5, and p38 MAPK after the activation of both the Abeta receptor(s) and mGluR5.
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