A number of recent studies have shown that beta-amyloid (Abeta) inhibits the induction of long-term potentiation (LTP) in the hippocampus. However, little is known about the mechanisms underlying such inhibition of LTP. In the present study, we present evidence that the cytokine tumor necrosis factor (TNF) alpha has a key role in the Abeta inhibition of LTP. The suppression of LTP by Abeta was absent in mutant mice null for TNF receptor type 1 (TNF-R1) and was prevented by the inhibitors of TNFalpha, infliximab and TNF peptide antagonist, and by the inhibitor of TNFalpha production, thalidomide. In addition, exogenous TNFalpha inhibited LTP induction, an action mediated via TNF-R1 as such inhibition was absent in mutant mice null for TNF-R1. The inhibition of LTP by TNFalpha involved activation of group I metabotropic glutamate receptor and p38 MAP kinase, identical to that for the Abeta-mediated inhibition of LTP induction.