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A High-Throughput Drug Screen Targeted to the 5'Untranslated Region of Alzheimer Amyloid Precursor Protein mRNA
1 Neurochemistry Laboratory, Genetics and Aging Research Unit, Psychiatry Department, Massachusetts General Hospital, Boston.
* To whom correspondence should be addressed. E-mail: jtrogers{at}rics.bwh.harvard.edu.
The authors employed a novel approach to identify therapeutics effective in Alzheimer disease (AD). The 5' untranslated region (5'UTR) of the mRNA of AD amyloid precursor protein (APP) is a significant regulator of the levels of the APP holo-protein and amyloid beta (A Key Words: Alzheimer disease, APP mRNA 5'UTR, HTS, luciferase, drugs, inhibitors
First published on April 28, 2006, doi:10.1177/1087057106287271 This article has been cited by other articles:
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) peptide in the central nervous system. The authors generated stable neuroblastoma SH-SY5Y transfectants that express luciferase under the translational control of the 146-nucleotide APP mRNA 5'UTR and green fluorescent protein (GFP) driven by a viral internal ribosomal entry site. Using a high-throughput screen (HTS), they screened for the effect of 110,000 compounds obtained from the library of the Laboratory for Drug Discovery on Neurodegeneration (LDDN) on the APP mRNA 5'UTR-controlled translation of the luciferase reporter. This screening yielded several nontoxic specific inhibitors of APP mRNA 5'UTR-driven luciferase that had no effect on the GFP expression in the stable SH-SY5Y transfectants. Moreover, these compounds either did not inhibit or inhibited to a much lower extent the expression of the luciferase reporter regulated by a prion protein (PrP) mRNA 5'UTR, used as an alternative mRNA structure to counterscreen APP mRNA 5'UTR in stably transfected SH-SY5Y cell lines. The hits obtained from this robust, specific, and highly quantitative HTS will be characterized to identify agents that may be developed into useful future therapeutic agents to limit APP translation and A
