Inhibition of cyclooxygenase as potential novel therapeutic strategy in N141I presenilin-2 familial Alzheimer's disease

W. Qin, Y. Peng, H. Ksiezak-Reding, L. Ho, B. Stetka, E. Lovati, G. M. Pasinetti

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25 Scopus citations


The present study was designed to further explore the potential cause/effect relationship between the expression of both the N141I presenilin (PS)2 mutant familial Alzheimer's disease (FAD) gene and cyclooxgenase (COX) in respect to the mechanism associated with programmed cell death in Alzheimer's disease (AD). We found that expression of mutant N141I PS2 resulting in apoptotic cell death in H4 neuronal cells coincided with >4-fold induction in the expression of the inducible form of COX-2, but not the constitutive COX-1. Moreover, we found that the expression of the N141I PS2 FAD gene strongly promoted (> 2-fold) glycogen synthase kinase (GSK)-3β activity coincidental with a reduction in the level of β-catenin translocated from the cytoplasmic to the nuclear compartment. Most interestingly, we found that inhibition of COX-2-mediated generation of prostaglandin (PG)-E2 in H4 neuronal cells with the preferential COX-2 inhibitor nimesulide protects against N141I PS2-mediated apoptotic cell death coincidental with an inhibition of GSK-3β activity and subsequent normalization of β-catenin cellular distribution. The clinical relevance of this finding was confirmed by the evidence that COX-2 protein and PG-E2 concentrations were selectively increased > 2-fold in the cerebral cortex of subjects harboring the N141I PS2 FAD mutation relative to wild-type PS2 AD cases. This study demonstrates for the first time that COX-2 may be a downstream effector of mutant N141I PS2-mediated apoptotic cell death and that inhibition of COX-2 may neuroprotect in AD through modulation of a GSK-3β-β-catenin-mediated response. The study provides support for the potential pharmacogenomic identification of N141I PS2 FAD cases that might preferentially benefit from inhibition of COX-2 during the progression of clinical dementia.

Original languageEnglish
Pages (from-to)172-181
Number of pages10
JournalMolecular Psychiatry
Issue number2
StatePublished - Feb 2006


  • Apoptosis
  • COX-2
  • GSK-3β
  • PS2
  • β-catenin


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