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 nm, 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 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 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.