Iwatsubo, Takeshi

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RNA Therapeutics and Abeta Precursor Protein Translation

Rogers, Jack T

1 August 2003 - 31 July 2007
NATIONAL INSTITUTE ON AGING
Total Funding: $ 1,192,021

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.

7 Resulting Publications

• 1.

  2006

  Stephanie Tucker; Michelle Ahl; Hyun-Hee Cho; Sanghamitra Bandyopadhyay; Gregory D Cuny; Ashley I Bush; Lee E Goldstein; David Westaway; Xudong Huang; Jack T Rogers

  RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine.

  Current Alzheimer research 2006;3(3):221-7.

• 2.

  2006

  S Bandyopadhyay; X Huang; H Cho; N H Greig; M B Youdim; J T Rogers

  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.

  Journal of neural transmission. Supplementum 2006;(71):237-47.

• 3.

  2005

  Stephanie Tucker; Michelle Ahl; Ashley Bush; David Westaway; Xudong Huang; Jack T Rogers

  Pilot study of the reducing effect on amyloidosis in vivo by three FDA pre-approved drugs via the Alzheimer's APP 5' untranslated region.

  Current Alzheimer research 2005;2(2):249-54.

• 4.

  2004

  Amanda Venti; Tony Giordano; Paul Eder; Ashley I Bush; Debomoy K Lahiri; Nigel H Greig; Jack T Rogers

  The integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5'-untranslated region.

  Annals of the New York Academy of Sciences 2004;1035():34-48.

• 5.

  2004

  Alpaslan Dedeoglu; Kerry Cormier; Sandra Payton; Katya A Tseitlin; Jonathan N Kremsky; Li Lai; Xiaohua Li; Robert D Moir; Rudolph E Tanzi; Ashley I Bush; et al.

  Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer's amyloidogenesis.

  Experimental gerontology 2004;39(11-12):1641-9.

• 6.

  2004

  Jack T Rogers; Debomoy K Lahiri

  Metal and inflammatory targets for Alzheimer's disease.

  Current drug targets 2004;5(6):535-51.

• 7.

  2004

  Lee Jae Morse; Sandra M Payton; Gregory D Cuny; Jack T Rogers

  FDA-preapproved drugs targeted to the translational regulation and processing of the amyloid precursor protein.

  Journal of molecular neuroscience : MN 2004;24(1):129-36.

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