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J. Biol. Chem., Vol. 277, Issue 35, 31466-31473, August 30, 2002
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From the § Eve Topf and National Parkinson
Foundation Centers of Excellence for Neurodegenerative
Diseases Research and Department of Pharmacology, Technion - Faculty
of Medicine, 31096 Haifa, Israel and ¶ Intradepartmental Unit
for Biotechnology, 31096 Haifa, Israel
Chronic inflammatory processes are associated
with the pathophysiology of Alzheimer's disease (AD), and it has been
proposed that treatment with non-steroidal anti-inflammatory drugs
(NSAIDs) reduces the risk for AD. Here we report that various NSAIDs,
such as the cyclooxygenase inhibitors, nimesulide, ibuprofen and
indomethacin, as well as thalidomide (Thal) and its non-teratogenic
analogue, supidimide, significantly stimulated the secretion of the
non-amyloidogenic
Non-steroidal Anti-inflammatory Drugs Stimulate Secretion
of Non-amyloidogenic Precursor Protein*
§¶,
-secretase form of the soluble amyloid precursor
protein (sAPP) into the conditioned media of SH-SY5Y neuroblastoma
and PC12 cells. These NSAIDs markedly reduced the levels of the
cellular APP holoprotein, further accelerating non-amyloidogenic
processes. sAPP release, induced by nimesulide and Thal, was
modulated by inhibitors of protein kinase C and Erk
mitogen-activated protein (MAP) kinase. Furthermore, in results
complementary to the inhibitor studies, we show for the first time that
NSAIDs can activate the Erk MAP kinase signaling cascade, thus
identifying a novel pharmacology mechanism of NSAIDs. Our findings
suggest that NSAIDs and Thal might prove useful to favor
non-amyloidogenic APP processing by enhancing -secretase activity,
thereby reducing the formation of amyloidogenic derivatives, and
therefore are of potential therapeutic value in AD.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Submitted in partial fulfillment of the M.Sc. degree requirements
of the Technion-Israel Institute of Technology.
To whom correspondence should be addressed: Dept. of
Pharmacology, Technion - Faculty of Medicine, P.O. Box 9697, 31096 Haifa, Israel, Tel.: 972-4-8295290; Fax: 972-4-8513145; E-mail:
youdim@tx.technion. ac.il.
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