Phenserine Regulates Translation of β-Amyloid Precursor Protein mRNA by a Putative Interleukin-1 Responsive Element, a Target for Drug Development

The reduction in levels of the potentially toxic amyloid-β peptide (Aβ) has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the expression and processing of the Aβ precursor protein (βAPP). Earlier reports from our...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2001-06, Vol.98 (13), p.7605-7610
Main Authors: Karen T. Y. Shaw, Utsuki, Tadanobu, Rogers, Jack, Yu, Qian-Sheng, Sambamurti, Kumar, Brossi, Arnold, Ge, Yuan-Wen, Lahiri, Debomoy K., Greig, Nigel H.
Format: Article
Language:English
Subjects:
5' Untranslated Regions - genetics
Amyloid beta-Protein Precursor - genetics
Antibodies
Astrocytoma
Biological Sciences
Cell lines
Cell Survival - drug effects
Chloramphenicol O-Acetyltransferase - analysis
Chloramphenicol O-Acetyltransferase - genetics
Cholinesterase Inhibitors - pharmacology
Chromones - pharmacology
Culture Media, Conditioned
Cytokines
Drug Design
drug development
Drug regulation
Enzyme Inhibitors - pharmacology
Flavonoids - pharmacology
Gene Expression Regulation - drug effects
Humans
Interleukin-1 - pharmacology
Interleukin-1 - physiology
L-Lactate Dehydrogenase - analysis
Messenger RNA
Mitogen-Activated Protein Kinases - metabolism
Morpholines - pharmacology
Neuroblastoma
Neurons
Peptides
Pharmacology
phenserine
Phosphatidylinositol 3-Kinases - metabolism
Physiological regulation
Physostigmine - analogs & derivatives
Physostigmine - pharmacology
Protein Biosynthesis - drug effects
Proteins
Recombinant Proteins - biosynthesis
Ribonucleic acid
RNA
RNA, Messenger - genetics
RNA, Messenger - metabolism
Transfection
Tumor Cells, Cultured
Untranslated regions
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Summary:The reduction in levels of the potentially toxic amyloid-β peptide (Aβ) has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the expression and processing of the Aβ precursor protein (βAPP). Earlier reports from our laboratory have shown that a novel cholinesterase inhibitor, phenserine, reduces βAPP levels in vivo. Herein, we studied the mechanism of phenserine's actions to define the regulatory elements in βAPP processing. Phenserine treatment resulted in decreased secretion of soluble βAPP and Aβ into the conditioned media of human neuroblastoma cells without cellular toxicity. The regulation of βAPP protein expression by phenserine was posttranscriptional as it suppressed βAPP protein expression without altering βAPP mRNA levels. However, phenserine's action was neither mediated through classical receptor signaling pathways, involving extracellular signal-regulated kinase or phosphatidylinositol 3-kinase activation, nor was it associated with the anticholinesterase activity of the drug. Furthermore, phenserine reduced expression of a chloramphenicol acetyltransferase reporter fused to the 5′-mRNA leader sequence of βAPP without altering expression of a control chloramphenicol acetyltransferase reporter. These studies suggest that phenserine reduces Aβ levels by regulating βAPP translation via the recently described iron regulatory element in the 5′-untranslated region of βAPP mRNA, which has been shown previously to be up-regulated in the presence of interleukin-1. This study identifies an approach for the regulation of βAPP expression that can result in a substantial reduction in the level of Aβ.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.131152998