Phenserine regulates translation of β-amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development

The reduction in levels of the potentially toxic amyloid-beta peptide (A beta) has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the expression and processing of the A beta precursor protein (beta APP). Earlier reports from our laboratory have shown that a novel cholinesterase inhibitor, phenserine, reduces beta APP levels in vivo. Herein, we studied the mechanism of phenserine's actions to define the regulatory elements in beta APP processing. Phenserine treatment resulted in decreased secretion of soluble beta APP and A beta into the conditioned media of human neuroblastoma cells without cellular toxicity. The regulation of beta APP protein expression by phenserine was posttranscriptional as it suppressed beta APP protein expression without altering beta APP mRNA levels. However, phenserine's action was neither mediated through classical receptor signaling pathways, involving extracellular signal-regulated kinase or phosphatidylinositol 3-kinase activation, nor was it associated with the anticholinesterase activity of the drug. Furthermore, phenserine reduced expression of a chloramphenicol acetyltransferase reporter fused to the 5 ' -mRNA leader sequence of beta APP without altering expression of a control chloramphenicol acetyltransferase reporter. These studies suggest that phenserine reduces A beta levels by regulating beta APP translation via the recently described iron regulatory element in the 5 ' -untranslated region of beta APP mRNA, which has been shown previously to be up-regulated in the presence of interleukin-1. This study identifies an approach for the regulation of beta APP expression that can result in a substantial reduction in the level of A beta.