Kty. 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
Citations number
48
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
The reduction in levels of the potentially toxic amyloid-beta peptide (A be
ta) has emerged as one of the most important therapeutic goals in Alzheimer
's disease. Key targets for this goal are factors that affect the expressio
n and processing of the A beta precursor protein (beta APP). Earlier report
s from our laboratory have shown that a novel cholinesterase inhibitor, phe
nserine, reduces beta APP levels in vivo. Herein, we studied the mechanism
of phenserine's actions to define the regulatory elements in beta APP proce
ssing. Phenserine treatment resulted in decreased secretion of soluble beta
APP and A beta into the conditioned media of human neuroblastoma cells wit
hout cellular toxicity. The regulation of beta APP protein expression by ph
enserine was posttranscriptional as it suppressed beta APP protein expressi
on without altering beta APP mRNA levels. However, phenserine's action was
neither mediated through classical receptor signaling pathways, involving e
xtracellular signal-regulated kinase or phosphatidylinositol 3-kinase activ
ation, nor was it associated with the anticholinesterase activity of the dr
ug. Furthermore, phenserine reduced expression of a chloramphenicol acetylt
ransferase reporter fused to the 5 ' -mRNA leader sequence of beta APP with
out altering expression of a control chloramphenicol acetyltransferase repo
rter. These studies suggest that phenserine reduces A beta levels by regula
ting beta APP translation via the recently described iron regulatory elemen
t in the 5 ' -untranslated region of beta APP mRNA, which has been shown pr
eviously to be up-regulated in the presence of interleukin-1. This study id
entifies an approach for the regulation of beta APP expression that can res
ult in a substantial reduction in the level of A beta.