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PMID: 15056716 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Block of long-term potentiation by naturally secreted and synthetic amyloid beta-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.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 24 ·No. 13 ·2004-03-31 ·Pages 3370-8

Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R

Abstract

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 approximately 1 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-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 Abeta. However, thealpha7 nicotinic ACh receptor antagonist methylcaconatine did not prevent the inhibition of LTP induction by Abeta. These studies provide evidence that the Abeta-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.

MeSH Terms
Amyloid beta-Peptides/genetics,metabolism,pharmacology Animals CHO Cells Cricetinae Cyclin-Dependent Kinase 5 Cyclin-Dependent Kinases/drug effects,metabolism Dose-Response Relationship, Drug Electric Stimulation/methods Enzyme Inhibitors/pharmacology Excitatory Amino Acid Antagonists/pharmacology Excitatory Postsynaptic Potentials/drug effects,physiology Female Hippocampus/drug effects,physiology Humans In Vitro Techniques JNK Mitogen-Activated Protein Kinases Long-Term Potentiation/drug effects,physiology Mitogen-Activated Protein Kinases/drug effects,metabolism Ovary/cytology,metabolism Peptide Fragments/genetics,metabolism,pharmacology Rats Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate/drug effects,metabolism p38 Mitogen-Activated Protein Kinases
Chemicals
Amyloid beta-Peptides Enzyme Inhibitors Excitatory Amino Acid Antagonists GRM5 protein, human Grm5 protein, rat Peptide Fragments Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate amyloid beta-protein (1-42) Cyclin-Dependent Kinase 5 CDK5 protein, human Cdk5 protein, rat Cyclin-Dependent Kinases JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Wang Qinwen
Department of Physiology and Pharmacology, Trinity College, Dublin 2, Ireland.
Walsh Dominic M
Rowan Michael J
Selkoe Dennis J
Anwyl Roger
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1633-03.2004
Published
2004-03-31
Pages
3370-8
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6730034
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 10.1523/JNEUROSCI.1633-03.2004 PMC Full Text View journal details
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