A number of recent studies have shown that β-amyloid (Aβ) 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) α has a key role in the Aβ inhibition of LTP. The suppression of LTP by Aβ was absent in mutant mice null for TNF receptor type 1 (TNF-R1) and was prevented by the inhibitors of TNFα, infliximab and TNF peptide antagonist, and by the inhibitor of TNFα production, thalidomide. In addition, exogenous TNFα 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 TNFα involved activation of group I metabotropic glutamate receptor and p38 MAP kinase, identical to that for the Aβ-mediated inhibition of LTP induction.