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.

Accumulation of cerebral amyloid ␤-protein (A␤) is believed to be part of the pathogenic process in Alzheimer's disease. A␤ is derived by proteolytic cleavage from a precursor protein, the amyloid precursor protein (APP). APP is a type-1 membrane-spanning protein, and its carboxyl-terminal intracellular domain binds to X11␤, a neuronal adaptor protein. X11␤ has been shown to inhibit the production of A␤ in transfected non-neuronal cells in culture. However, whether this is also the case in vivo in the brain and whether X11␤ can also inhibit the deposition of A␤ as amyloid plaques is not known. Here we show that transgenic overexpression of X11␤ in neurons leads to a decrease in cerebral A␤ levels in transgenic APPswe Tg2576 mice that are a model of the amyloid pathology of Alzheimer's disease. Moreover, overexpression of X11␤ retards amyloid plaque formation in these APPswe mice. Our findings suggest that modulation of X11␤ function may represent a novel therapeutic approach for preventing the amyloid pathology of Alzheimer's disease.X11␤ (also known as munc-18-interacting protein-2; mint-2) is a neuronal adaptor protein involved in the formation of multiprotein complexes in the brain. To fulfill this function, X11␤ contains a number of protein-protein interaction domains through which it binds specific ligands. These include aminoterminal sequences that bind munc-18 and a novel protein XB51 (1-3), two carboxyl-terminal PDZ domains that bind presenilin-1 (4, 5), neurexins (6), and NF-B/p65 (7), and a centrally located PTB domain that binds to the Alzheimer's disease amyloid precursor protein (APP) 1 (8 -11). APP is a type-1 membrane protein that is proteolytically processed to produce secreted derivatives, and one of these is the 40 -42-amino-acid A␤ peptide that is deposited within amyloid plaques in the brains of patients with Alzheimer's disease.Cleavage of APP to release A␤ involves sequential proteolysis by ␤-secretase (BACE1) and ␥-secretase (presenilin/nicastrin/ Aph-1/Pen-2); alternative cleavage by ␣-secretase within the A␤ sequence precludes A␤ production (12)(13)(14). Aberrant processing of APP leading to the increased production of A␤ is believed to contribute to Alzheimer's disease. In particular, the increased production of the longer A␤(1-42) species is thought to be an early pathogenic event in Alzheimer's disease (13).X11␤ is part of a small family of related proteins that also include X11␣ and X11␥; X11␤ and X11␣ are neuronal (15). Both X11␣ and X11␤ inhibit the production of A␤ in transfected non-neuronal cells (16 -18), and recently, X11␣ has been shown to inhibit the production and deposition of A␤ in the brains of transgenic mice (19). However, similar in vivo transgenic studies have not been performed for X11␤, and this represents a major omission. This is because neurons can process APP to produce A␤ differently from cell lines in culture (20 -23) and because the deposition of A␤ can only be studied properly in vivo in the brain.Likewise, it is important to study the effects of both X11␤ ...