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

The reduction in levels of the potentially toxic amyloid-beta peptide (A be ta) has emerged as one of the most important therapeutic goals in Alzheimer 's disease. Key targets for this goal are factors that affect the expressio n and processing of the A beta precursor protein (beta APP). Earlier report s from our laboratory have shown that a novel cholinesterase inhibitor, phe nserine, reduces beta APP levels in vivo. Herein, we studied the mechanism of phenserine's actions to define the regulatory elements in beta APP proce ssing. Phenserine treatment resulted in decreased secretion of soluble beta APP and A beta into the conditioned media of human neuroblastoma cells wit hout cellular toxicity. The regulation of beta APP protein expression by ph enserine was posttranscriptional as it suppressed beta APP protein expressi on without altering beta APP mRNA levels. However, phenserine's action was neither mediated through classical receptor signaling pathways, involving e xtracellular signal-regulated kinase or phosphatidylinositol 3-kinase activ ation, nor was it associated with the anticholinesterase activity of the dr ug. Furthermore, phenserine reduced expression of a chloramphenicol acetylt ransferase reporter fused to the 5 ' -mRNA leader sequence of beta APP with out altering expression of a control chloramphenicol acetyltransferase repo rter. These studies suggest that phenserine reduces A beta levels by regula ting beta APP translation via the recently described iron regulatory elemen t in the 5 ' -untranslated region of beta APP mRNA, which has been shown pr eviously to be up-regulated in the presence of interleukin-1. This study id entifies an approach for the regulation of beta APP expression that can res ult in a substantial reduction in the level of A beta.