It has been shown that Aβ inhibits long-term potentiation (LTP) in the rat hippocampus and this is accompanied by an increase in hippocampal concentration of IL-1β. Aβ also increases microglial activation, which is the likely cell source of IL-1β. Because IL-4 attenuates the effects of IL-1β in hippocampus, and microglial activation is inhibited by minocycline, we assessed the ability of both IL-4 and minocycline to modulate the effects of Aβ on LTP and IL-1β concentration. Following treatment with Aβ, IL-4 or minocycline, rats were assessed for their ability to sustain LTP in perforant path-granule cell synapses. We report that the Aβ-induced inhibition of LTP was associated with increases in expression of MHCII, JNK phosphorylation and IL-1β concentration, and that these changes were attenuated by treatment of rats with IL-4 and minocycline. We also report that Aβ-induced increases in expression of MHCII and IL-1β were similarly attenuated by IL-4 and minocycline in glial cultures prepared from neonatal rats. These data suggest that glial cell activation and the consequent increase in IL-1β concentration mediate the inhibitory effect of Aβ on LTP and indicate that IL-4, by down-regulating glial cell activation, antagonizes the effects of Aβ.