COREGULATION OF APP AND FERRITIN MRNAS AND APP FUNCTION

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IL-1 and Iron co-regulation of the ferritin and APP genes should shed light on the unexplored true function of the ubiquitous chromosome 21 APP protein which is the main pathogenic contributor to Alzheimer's disease. Two features of APP biology should shed light on the role of this abundant membrane protein. First, the APP gene, like the gene for the iron storage protein ferritin, is regulated at the translational level in response to IL-1 and iron (Rogers, 1996, and Submitted). The APP-mRNA 5' untranslated region (5'UTR) is related to the L and H- ferritin mRNA 5'UTR, including a conserved placement of both Iron responsive elements (IREs) and powerful IL-1 responsive RNA sequences. Iron releases ferritin mRNAs from translational repression by removal of an IRE-binding protein (IRP, iron regulatory protein) from the 5' cap site IRE. Altered interaction between IRPs and 5'UTR sequences in APP- mRNA regulates APP translation in response IL-1 signals and intracellular iron levels. Second, preliminary evidence indicates that APP directly interacts with ferritin in the cytoplasm of astrocytoma cells. We will: 1. explore the action of an "IRE-like" RNA stem-loop in front of the APP-mRNA start codon which, like ferritin mRNA IREs, can interact with the IRE-binding proteins (Iron Regulatory Proteins, IRPs). 2. examine whether the L- or the H-ferritin interacts with APP protein in astrocytes and astrocytoma cells and examine APP protein for ferroxidase activity.