Alzheimer's disease drug discovery targeted to the APP mRNA 5′untranslated region

J. T. Rogers, J. D. Randall, P. S. Eder, X. Huang, A. I. Bush, R. E. Tanzi, A. Venti, S. M. Payton, T. Giordano, S. Nagano, C. M. Cahill, R. Moir, D. K. Lahiri, N. Greig, S. S. Sarang, S. R. Gullans

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

We performed a screen for drugs that specifically interact with the 5′ untranslated region of the mRNA coding for the Alzheimer's Amyloid Precursor Protein (APP). Using a transfection based assay, in which APP 5′UTR sequences drive the translation of a downstream luciferase reporter gene, we have been screening for new therapeutic compounds that already have FDA approval and are pharmacologically and clinically well-characterized. Several classes of FDA-pre-approved drugs (16 hits) reduced APP 5′UTR-directed luciferase expression (> 95% inhibition of translation). The classes of drugs include known blockers of receptor ligand interactions, bacterial antibiotics, drugs involed in lipid metabolism, and metal chelators. These APP 5′UTR directed drugs exemplify a new strategy to identify RNA-directed agents to lower APP translation and Aβ peptide output for Alzheimer's disease therapeutics.

Original languageEnglish (US)
Pages (from-to)77-82
Number of pages6
JournalJournal of Molecular Neuroscience
Volume19
Issue number1-2
DOIs
StatePublished - Jan 1 2002

Keywords

  • Alzheimer's disease
  • APP mRNA 5′untranslated region
  • Drug screen
  • FDA-2000 Drug library
  • RNA-targeting
  • Translation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry
  • Genetics

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    Rogers, J. T., Randall, J. D., Eder, P. S., Huang, X., Bush, A. I., Tanzi, R. E., Venti, A., Payton, S. M., Giordano, T., Nagano, S., Cahill, C. M., Moir, R., Lahiri, D. K., Greig, N., Sarang, S. S., & Gullans, S. R. (2002). Alzheimer's disease drug discovery targeted to the APP mRNA 5′untranslated region. Journal of Molecular Neuroscience, 19(1-2), 77-82. https://doi.org/10.1007/s12031-002-0014-6