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Titolo:
Phenserine regulates translation of beta-amyloid precursor protein mRNA bya putative interleukin-1 responsive element, a target for drug development
Autore:
Shaw, KTY; Utsuki, T; Rogers, J; Yu, QS; Sambamurti, K; Brossi, A; Ge, YW; Lahiri, DK; Greig, NH;
Indirizzi:
NIA, Drug Design & Dev, Neurosci Lab, Baltimore, MD 21224 USA NIA Baltimore MD USA 21224 n & Dev, Neurosci Lab, Baltimore, MD 21224 USA Harvard Univ, Sch Med, Genet Aging Unit, Boston, MA 02115 USA Harvard Univ Boston MA USA 02115 , Genet Aging Unit, Boston, MA 02115 USA Mayo Clin, Dept Pharmacol, Jacksonville, FL 32224 USA Mayo Clin Jacksonville FL USA 32224 Pharmacol, Jacksonville, FL 32224 USA Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 ychiat, Indianapolis, IN 46202 USA
Titolo Testata:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
fascicolo: 13, volume: 98, anno: 2001,
pagine: 7605 - 7610
SICI:
0027-8424(20010619)98:13<7605:PRTOBP>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
SYNTHASE MESSENGER-RNA; ALZHEIMERS-DISEASE; KINASE-C; PHORBOL ESTER; MITOCHONDRIAL ACONITASE; 5'-UNTRANSLATED REGION; NEUROBLASTOMA-CELLS; SECRETASE CLEAVAGE; RETINOIC ACID; HUMAN BRAIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
48
Recensione:
Indirizzi per estratti:
Indirizzo: Greig, NH NIA, Drug Design & Dev, Neurosci Lab, Baltimore, MD 21224 USA NIA Baltimore MD USA 21224 eurosci Lab, Baltimore, MD 21224 USA
Citazione:
K.T.Y. Shaw et al., "Phenserine regulates translation of beta-amyloid precursor protein mRNA bya putative interleukin-1 responsive element, a target for drug development", P NAS US, 98(13), 2001, pp. 7605-7610

Abstract

The reduction in levels of the potentially toxic amyloid-beta peptide (A beta) 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 A beta precursor protein (beta APP). Earlier reports from our laboratory have shown that a novel cholinesterase inhibitor, phenserine, reduces beta APP levels in vivo. Herein, we studied the mechanismof phenserine's actions to define the regulatory elements in beta APP processing. Phenserine treatment resulted in decreased secretion of soluble beta APP and A beta into the conditioned media of human neuroblastoma cells without cellular toxicity. The regulation of beta APP protein expression by phenserine was posttranscriptional as it suppressed beta APP protein expression without altering beta APP mRNA levels. However, phenserine's action wasneither 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 beta APP without altering expression of a control chloramphenicol acetyltransferase reporter. These studies suggest that phenserine reduces A beta levels by regulating beta APP translation via the recently described iron regulatory element in the 5 ' -untranslated region of beta APP 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 beta APP expression that can result in a substantial reduction in the level of A beta.

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Documento generato il 05/04/20 alle ore 06:45:47