RNA Therapeutics and Abeta Precursor Protein Translation

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DESCRIPTION (provided by applicant): The Alzheimer's Amyloid Precursor Protein (APP), like ferritin, is a ubiquitously expressed metaloprotein that is regulated at the level of message translatation. We showed that the primary inflammatory cytokine, Interleukin-1 (IL-1), up-regulated APP synthesis by up to 15-fold in the complete absence of changes to steady-state levels of APP mRNA. IL-1 and iron levels significantly regulate APP-mRNA translation (and ABeta peptide levels) correlated with changed interaction between Iron Regulatory Protein (IRPs) and APP 5'UTR sequences (IRE-Type II sequences). Iron influx is known to release ferritin mRNAs from translational repression by removal of IRP from 5' untranslated region specific RNA stemloops that are related to APP 5'UTR sequences. Understanding regulation conferred by the APP 5'UTR will enable us to better identify medicinal compounds that reduce APP translation and Abeta-peptide levels. RNA-directed strategies have recently been developed for the use of small molecules to suppress viral infections, including a strategy to target the internal ribosome entry site Hepatitis-C virus. The iron chlelator desferrioxamine (Df) (Mw 650) and the novel anticholinesterase, phenserine (Ps) (Mw 480) suppress APP 5'UTR driven translation of APP to reduce amyloid output, exemplifying the use of this sequence as a therapeutic target for Alzheimer's disease. We will: 1. Define the location and functional action of cis-acting IL-1- and iron-responsive RNA enhancers in APP mRNA and examine functional interactions between 5'UTR and 3'UTR sequences. 2. Determine how the unique folding of RNA encoded by the APP 5'UTR offers a therapeutic target for small molecules exemplified by desferrioxamine and the anticholinesterase, phenserine. 3. Test the hypothesis that altering the binding of Iron-regulatory proteins (IRP-1 and IRP-2) to RNA structures in APP 5"UTR mediates IL-1 signals to increase APP translation. Small molecules could well act by this pathway to decrease APP synthesis and concomitant ABeta-peptide output.