Novel role for COX2 inhibitors in the treatment of N141I PSEN2 familial Alzheimer's disease?

Qin W et al. (2006) Inhibition of cyclooxygenase as potential novel therapeutic strategy in N141I presenilin-2 familial Alzheimer's disease. Mol Psychiatry 11: 172–181

Evidence from epidemiological studies suggesting a potential protective effect of anti-inflammatory drugs in Alzheimer's disease (AD) have not been supported by therapeutic studies using nonsteroidal anti-inflammatory drugs. To further investigate the role of anti-inflammatory drugs in familial AD (FAD), a group led by Pasinetti studied the potential association between cyclooxygenase (COX) and AD pathogenesis in neuronal cell lines expressing mutant N141I presenilin-2 (PSEN2). These associations were then studied in the brains of patients harboring the mutation.

N141I PSEN2 expression was found to coincide with a greater than fourfold increase in expression of the inducible form of COX2 but not in the constitutively expressed COX1, and with a subsequent increase in the generation of COX2-derived prostaglandin E₂ in neuronal cells. Similar responses were found in the brains of FAD cases harboring N141I PSEN2 mutations. The expression of the N141I PSEN2 FAD gene strongly promoted glycogen synthase kinase-3β activity coincidental with a reduction in the level of β-catenin translocated from the cytoplasm to the nucleus. Inhibition of COX2-mediated generation of prostaglandin E₂ in the neuronal cells using nimesulide, a preferential COX2 inhibitor, protected against N141I PSEN2-mediated apoptotic neuronal cell death. This protection was associated with inhibition of glycogen synthase kinase-3β activity and subsequent normalization of β-catenin distribution.

The study provides support for the potential pharmacogenomic identification of N141I PSEN2 FAD cases that might be most likely to benefit from inhibition of COX2 during the progression of clinical FAD dementia.