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

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 involved 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 A beta peptide output for Alzheimer's disease therapeutics.

• Authors: Jack T Rogers, Jeffrey D Randall, Paul S Eder, Xudong Huang, Ashley I Bush, Rudolph E Tanzi, Amanda Venti, Sandra M Payton, Tony Giordano, Seiichi Nagano, Catherine M Cahill, Robert Moir, Debomoy K Lahiri, Nigel Greig, Satinder Singh Sarang, Steven R Gullans
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) 2002 Aug-Oct Vol. 19 Issue 1-2 Pg. 77-82 ISSN: 0895-8696 [Print] United States
• PMID: 12212798 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 5' Untranslated Regions
• Amyloid beta-Protein Precursor
• Pharmaceutical Preparations
• RNA, Messenger
• Luciferases

Topics

• 5' Untranslated Regions (drug effects)
• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Protein Precursor (drug effects, genetics, metabolism)
• Drug Approval
• Humans
• Luciferases (genetics)
• Pharmaceutical Preparations
• Protein Biosynthesis
• RNA, Messenger (drug effects)
• Transfection
• Tumor Cells, Cultured
• United States