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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Snyder, Stephen D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Bandyopadhyay, Sanghamitra; Rogers, Jack T (2014) Alzheimer's disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis. Biochem Pharmacol 88:486-94
Bandyopadhyay, Sanghamitra; Huang, Xudong; Lahiri, Debomoy K et al. (2010) Novel drug targets based on metallobiology of Alzheimer's disease. Expert Opin Ther Targets 14:1177-97
Bandyopadhyay, S; Huang, X; Cho, H et al. (2006) Metal specificity of an iron-responsive element in Alzheimer's APP mRNA 5'untranslated region, tolerance of SH-SY5Y and H4 neural cells to desferrioxamine, clioquinol, VK-28, and a piperazine chelator. J Neural Transm Suppl :237-47
Tucker, Stephanie; Ahl, Michelle; Cho, Hyun-Hee et al. (2006) RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine. Curr Alzheimer Res 3:221-7
Tucker, Stephanie; Ahl, Michelle; Bush, Ashley et al. (2005) Pilot study of the reducing effect on amyloidosis in vivo by three FDA pre-approved drugs via the Alzheimer's APP 5' untranslated region. Curr Alzheimer Res 2:249-54
Rogers, Jack T; Lahiri, Debomoy K (2004) Metal and inflammatory targets for Alzheimer's disease. Curr Drug Targets 5:535-51
Dedeoglu, Alpaslan; Cormier, Kerry; Payton, Sandra et al. (2004) Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer's amyloidogenesis. Exp Gerontol 39:1641-9
Venti, Amanda; Giordano, Tony; Eder, Paul et al. (2004) The integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5'-untranslated region. Ann N Y Acad Sci 1035:34-48
Morse, Lee Jae; Payton, Sandra M; Cuny, Gregory D et al. (2004) FDA-preapproved drugs targeted to the translational regulation and processing of the amyloid precursor protein. J Mol Neurosci 24:129-36