Cited by 437Neuroscience and Neuropharmacology ResearchAlzheimer's disease research and treatmentsMemory and Neural Mechanisms

Block of Long-Term Potentiation by Naturally Secreted and Synthetic Amyloid β-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

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Wang, Qinwen, Walsh, Dominic M., Rowan, Michael J., Selkoe, Dennis J., Anwyl, Roger·2004·The Journal of Neuroscience

Abstract

The mechanisms of action of human synthetic and naturally secreted cell-derived amyloid β-peptide (Aβ)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 Aβ strongly inhibited high-frequency stimulation (HFS)-induced LTP at peak HFS and 1 hr after HFS. Cell-derived Aβ was much more potent than synthetic Aβ at inhibiting LTP induction, with threshold concentrations of ∼1 and 100–200 n m, respectively. The involvement of various kinases in Aβ-mediated inhibition of LTP induction was investigated by applying Aβ 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 Aβ. The block of LTP induced by synthetic Aβ 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 2 S-2-amino-2-(1 S,2 S-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 Aβ. However, theα7 nicotinic ACh receptor antagonist methylcaconatine did not prevent the inhibition of LTP induction by Aβ. These studies provide evidence that the Aβ-mediated inhibition of LTP induction involves stimulation of the kinases JNK, Cdk5, and p38 MAPK after the activation of both the Aβ receptor(s) and mGluR5.

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Crossref · 10.1523/jneurosci.1633-03.2004

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Authors
Wang, Q., Walsh, D. M., Rowan, M. J., Selkoe, D. J., & Anwyl, R.
Affiliations
  • Trinity College Dublin (IE)
  • Brigham and Women's Hospital (US)
Corresponding author
Anwyl, Roger
Venue
The Journal of Neuroscience
Published
2004-03-31
Volume
24
Issue
13
Pages
3370-3378
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2001900724
Cited by
437
References
69
Citations by year
2026: 5 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 12 · 2021: 12 · 2020: 15 · 2019: 8 · 2018: 12 · 2017: 16 · 2016: 27 · 2015: 21 · 2014: 28 · 2013: 21 · 2012: 34
FWCI
10.78
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust
  • National Institutes of Health
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
amyloid-beta, long-term potentiation, c-Jun N-terminal kinase, cyclin-dependent kinase 5, p38 MAPK, metabotropic glutamate receptor 5, dentate gyrus, perforant path, high-frequency stimulation, kinase inhibitors, Alzheimer's disease, synaptic plasticity, hippocampus, butyrolactone, roscovitine, dents
MeSH terms
Animals, Dose-Response Relationship, Drug, Electric Stimulation, Enzyme Inhibitors, Female, Cricetinae, Hippocampus, Humans, Ovary, Peptide Fragments, Amyloid beta-Peptides, CHO Cells, Long-Term Potentiation, Receptors, Metabotropic Glutamate, Excitatory Amino Acid Antagonists, Cyclin-Dependent Kinases, Excitatory Postsynaptic Potentials, Mitogen-Activated Protein Kinases, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Cyclin-Dependent Kinase 5, Rats, Receptor, Metabotropic Glutamate 5, In Vitro Techniques

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