Cyclooxygenase-2 inhibition improves amyloid-β-mediated suppression of memory and synaptic plasticity

Non-steroidal anti-inflammatory agents (NSAIDs) are associated with a marked reduction in the risk of developing Alzheimers disease, a form of dementia characterized by the accumulation of amyloid plaques containing the amyloid-beta protein (A). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of A beta from the amyloid precursor protein (APP) have led to two proposed mechanisms by which NSAIDs may protect against Alzheimers disease: one, the selective lowering of A beta 42 by a subset of NSAIDs; and two, the reduction of inflammation. Although Alzheimers disease is a disorder of brain and synaptic function, the effects of NSAIDs on A beta-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 A beta 42 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 A beta-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 A beta. 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 A beta-mediated inhibition of LTP. There was no advantage of ibuprofen, a selective A beta 42-lowering agent (SALA), over the non-SALAs, naproxen and MF-tricyclic. The beneficial effects on memory did not depend upon lowered levels of A42 or the inflammatory cytokines, tumour necrosis factor (TNF-alpha) and interleukin 1 beta (IL-1 beta). 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 A beta-mediated suppression of LTP and memory function, and that this block occurs independently of reductions in A beta 42 or decreases in inflammation. The results lead us to propose a third possible mechanism by which NSAIDs may protect against Alzheimers disease, involving the blockade of a COX-2-mediated PGE2 response at synapses.