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The Journal of Neuroscience, March 31, 2004, 24(13):3370-3378; doi:10.1523/JNEUROSCI.1633-03.2004
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Development/Plasticity/Repair
Block of Long-Term Potentiation by Naturally Secreted and Synthetic Amyloid  -Peptide in Hippocampal Slices Is Mediated via Activation of the Kinases c-Jun N-Terminal Kinase, Cyclin-Dependent Kinase 5, and p38 Mitogen-Activated Protein Kinase as well as Metabotropic Glutamate Receptor Type 5
Qinwen Wang,1
Dominic M. Walsh,3
Michael J. Rowan,2
Dennis J. Selkoe,3 and
Roger Anwyl1
Departments of 1Physiology and Pharmacology and 2Therapeutics, Trinity College, Dublin 2, Ireland, and 3Department of Neurology, Harvard Medical School and Center for Neurologic Disease, Brigham and Women's Hospital, Boston, Massachusetts 02115
The mechanisms of action of human synthetic and naturally secreted cell-derived amyloid  -peptide (A)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 A strongly inhibited high-frequency stimulation (HFS)-induced LTP at peak HFS and 1 hr after HFS. Cell-derived A was much more potent than synthetic A at inhibiting LTP induction, with threshold concentrations of  1 and 100–200 nM, respectively. The involvement of various kinases in A-mediated inhibition of LTP induction was investigated by applying A 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 A. The block of LTP induced by synthetic A 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-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)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 by A. However, the 7 nicotinic ACh receptor antagonist methylcaconatine did not prevent the inhibition of LTP induction by A. These studies provide evidence that the A-mediated inhibition of LTP induction involves stimulation of the kinases JNK, Cdk5, and p38 MAPK after the activation of both the A receptor(s) and mGluR5.
Key words: amyloid -protein; LTP; metabotropic glutamate receptors; hippocampus; JNK; Cdk5; p38 MAPK; Alzheimer's disease
Received July 29, 2003;
revised January 21, 2004;
accepted February 2, 2004.
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