Alzheimer's disease is a neurodegenerative disorder affecting the elderly and accounts for two thirds of all dementia. Recent epidemiological studies suggest that the use of non-steroidal anti-inflammatory agents is associated with a significantly lower risk of developing Alzheimer's disease. The primary targets of NSAIDs are the prostaglandin synthases, also known as cyclooxygenases. The cyclooxygenases catalyze the conversion of arachidonic acid to PGH2, which becomes the substrate for prostaglandin and thromboxane synthases. The conclusion raised by the recent epidemiological studies is that inhibition of cyclooxygenases activity is protective against development of Alzheimer's disease. There are two isoforms of cyclooxygenase (cox). Cox-1 is expressed constitutively in most tissues and at very low levels in the brain. Cox-2 is expressed in neurons of hipppocampus, amygdala and layers II/III of cortex. From our previous studies of genes involved in the adaptive responses of neurons to synaptic activity, we have identified cox-2 as an N-methyl D-aspartate (NMDA)-dependent activity-regulated gene in brain. Cox-2 is also highly expressed in neurons in paradigms of excitotoxicity, such as ischemia, trauma, and kindling. Because of its regulation by excitatory synaptic activity, and because of recent evidence implicating excitotoxic mechanisms in neurodegenerative diseases, we propose to study the role of cox-2 in the pathogenesis of Alzheimer's disease. We have generated transgenic C57Bl6/J founder mice that express the human form of cox-2 driven by the neuronal specific thy-1. An initial line of transgenic hcox-2 mice demonstrates immunoreactive hcox-2 and an 8 to 12-fold increase in PGE2 synthesis.
In Aim 1 we will complete our immunohistochemical and biochemical characterization of remaining lines generated from our founder mice and select 3-5 additional lines for further study.
In Aim 2 we will examine the contribution of cox-2 activity to the pathogenesis of Alzheimer's disease by crossing hcox-2 mice to a murine model of familial Alzheimer's disease that overexpresses mutant APP and PS-1 and analyzing the pathological phenotype of resultant double and triple transgenic mice.
In Aim 3, we will test the effect of a selective cox-2 inhibitor on the development of a pathological AD phenotype in single, bigenic and trigenic mice generated in Aims 1 and 2.
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