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

Linda A. Kotilinek, Marcus A. Westerman, Qinwen Wang, Kimberly Panizzon, Giselle P. Lim, Agnes Simonyi, Sylvain E Lesne, Agnieszka Falinska, Linda H. Younkin, Steven G. Younkin, Michael Rowan, James Cleary, Roi Ann Wallis, Grace Y. Sun, Greg Cole, Sally Frautschy, Roger Anwyl, Karen H Ashe

Research output: Contribution to journalArticle

157 Citations (Scopus)

Abstract

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-β protein (Aβ). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of Aβ 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 Aβ42 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 Aβ-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 Aβ42 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 Aβ-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 Aβ. 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 Aβ-mediated inhibition of LTP. There was no advantage of ibuprofen, a selective Aβ42-lowering agent (SALA), over the non-SALAs, naproxen and MF-tricyclic. The beneficial effects on memory did not depend upon lowered levels of Aβ42 or the inflammatory cytokines, tumour necrosis factor α (TNF-α) and interleukin 1β (IL-1β). 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 Aβ-mediated suppression of LTP and memory function, and that this block occurs independently of reductions in Aβ42 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.

Original languageEnglish (US)
Pages (from-to)651-664
Number of pages14
JournalBrain
Volume131
Issue number3
DOIs
StatePublished - Mar 1 2008

Fingerprint

Neuronal Plasticity
Non-Steroidal Anti-Inflammatory Agents
Cyclooxygenase 2
Amyloid
Serum Amyloid A Protein
Alzheimer Disease
Dinoprostone
Cyclooxygenase 1
Naproxen
Amyloid beta-Protein Precursor
Cyclooxygenase 2 Inhibitors
Ibuprofen
Amyloid Plaques
Synapses
Inhibition (Psychology)
Inflammation
Long-Term Memory
Brain Diseases
Risk Reduction Behavior
Prostaglandin-Endoperoxide Synthases

Keywords

  • Inflammation
  • Memory
  • NSAIDs
  • Synaptic plasticity
  • Transgenic

Cite this

Kotilinek, L. A., Westerman, M. A., Wang, Q., Panizzon, K., Lim, G. P., Simonyi, A., ... Ashe, K. H. (2008). Cyclooxygenase-2 inhibition improves amyloid-β-mediated suppression of memory and synaptic plasticity. Brain, 131(3), 651-664. https://doi.org/10.1093/brain/awn008

Cyclooxygenase-2 inhibition improves amyloid-β-mediated suppression of memory and synaptic plasticity. / Kotilinek, Linda A.; Westerman, Marcus A.; Wang, Qinwen; Panizzon, Kimberly; Lim, Giselle P.; Simonyi, Agnes; Lesne, Sylvain E; Falinska, Agnieszka; Younkin, Linda H.; Younkin, Steven G.; Rowan, Michael; Cleary, James; Wallis, Roi Ann; Sun, Grace Y.; Cole, Greg; Frautschy, Sally; Anwyl, Roger; Ashe, Karen H.

In: Brain, Vol. 131, No. 3, 01.03.2008, p. 651-664.

Research output: Contribution to journalArticle

Kotilinek, LA, Westerman, MA, Wang, Q, Panizzon, K, Lim, GP, Simonyi, A, Lesne, SE, Falinska, A, Younkin, LH, Younkin, SG, Rowan, M, Cleary, J, Wallis, RA, Sun, GY, Cole, G, Frautschy, S, Anwyl, R & Ashe, KH 2008, 'Cyclooxygenase-2 inhibition improves amyloid-β-mediated suppression of memory and synaptic plasticity', Brain, vol. 131, no. 3, pp. 651-664. https://doi.org/10.1093/brain/awn008
Kotilinek LA, Westerman MA, Wang Q, Panizzon K, Lim GP, Simonyi A et al. Cyclooxygenase-2 inhibition improves amyloid-β-mediated suppression of memory and synaptic plasticity. Brain. 2008 Mar 1;131(3):651-664. https://doi.org/10.1093/brain/awn008
Kotilinek, Linda A. ; Westerman, Marcus A. ; Wang, Qinwen ; Panizzon, Kimberly ; Lim, Giselle P. ; Simonyi, Agnes ; Lesne, Sylvain E ; Falinska, Agnieszka ; Younkin, Linda H. ; Younkin, Steven G. ; Rowan, Michael ; Cleary, James ; Wallis, Roi Ann ; Sun, Grace Y. ; Cole, Greg ; Frautschy, Sally ; Anwyl, Roger ; Ashe, Karen H. / Cyclooxygenase-2 inhibition improves amyloid-β-mediated suppression of memory and synaptic plasticity. In: Brain. 2008 ; Vol. 131, No. 3. pp. 651-664.
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AU - Kotilinek, Linda A.

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AU - Lim, Giselle P.

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AU - Younkin, Steven G.

AU - Rowan, Michael

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