Non-steroidal anti-inflammatory agents (NSAIDs) are associated with a marked reduction in the risk of developing Alzheimer's disease, a form of dementia characterized by the accumulation of amyloid plaques containing the amyloid-beta protein (Abeta). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of Abeta from the amyloid precursor protein (APP) have led to two proposed mechanisms by which NSAIDs may protect against Alzheimer's disease: one, the selective lowering of Abeta42 by a subset of NSAIDs; and two, the reduction of inflammation. Although Alzheimer's disease is a disorder of brain and synaptic function, the effects of NSAIDs on Abeta-mediated suppression of synaptic plasticity and memory function have never been reported. We therefore investigated how three different NSAIDs, chosen for their distinct effects on Abeta42 production and the inhibition of the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, affect memory function and synaptic plasticity. By focusing upon brain and synapse function, we made novel observations about the effects of NSAIDs on Abeta-mediated neural processes. Here we report that the selective inhibition of COX-2, but not COX-1, acutely prevented the suppression of hippocampal long-term plasticity (LTP) by Abeta. The non-selective NSAIDs, ibuprofen and naproxen, and a selective COX-2 inhibitor, MF-tricyclic, each restored memory function in Tg2576 mice over-expressing APP, and also blocked Abeta-mediated inhibition of LTP. There was no advantage of ibuprofen, a selective Abeta42-lowering agent (SALA), over the non-SALAs, naproxen and MF-tricyclic. The beneficial effects on memory did not depend upon lowered levels of Abeta42 or the inflammatory cytokines, tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Intriguingly, improved memory function was inversely related to prostaglandin E2 (PGE2) levels. Conversely, exogenous PGE2 prevented the restorative effects of COX-2 inhibitors on LTP. The data indicate that the inhibition of COX-2 blocks Abeta-mediated suppression of LTP and memory function, and that this block occurs independently of reductions in Abeta42 or decreases in inflammation. The results lead us to propose a third possible mechanism by which NSAIDs may protect against Alzheimer's disease, involving the blockade of a COX-2-mediated PGE2 response at synapses.