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Cyclic nucleotide signaling controls a wide variety of cellular functions. Phosphodiesterases (PDEs) regulate the intracellular levels of cAMP and cGMP, thus playing an important role in signal transduction. It has been observed that PDE4 inhibition is important for the regulation of cAMP levels in most cells involved in inflammatory processes. It has been hypothesized that inflammation is a primary process in the pathogenesis of Alzheimer's disease (AD). Based on this and by using in situ hybridization histochemistry, we have analyzed the cellular expression pattern of several cAMP-specific phosphodiesterases in different brain regions in control subjects and in patients with Alzheimer's disease. By combining in situ hybridization with immunohistochemistry, we have studied the neuronal and non-neuronal nature of the cells expressing several PDE isozymes, and focused our attention on their relation with senile plaques accumulation stained with Thioflavine S. We have observed some changes in the expression levels of the mRNAs coding for PDE4 and PDE8B isozymes in Alzheimer's disease brains at different stages of the disease. We found that in the entorhinal cortex, the proportion of neurons and glial cells that express PDE4B mRNA in control brains is almost reversed in the brains of Alzheimer patients. Our aim is to try to elucidate the molecular modifications associated with senile plaques, and help to establish the scientific background supporting the therapeutic use of selective cAMP-phosphodiesterase inhibitors in Alzheimer's disease. |
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