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 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.
Wang
Qinwen
Q
Department of Physiology and Pharmacology, Trinity College, Dublin 2, Ireland.
Walsh
Dominic M
DM
Rowan
Michael J
MJ
Selkoe
Dennis J
DJ
Anwyl
Roger
R
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D010446:Peptide Fragments; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C075222:amyloid beta-protein (1-42); D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases