Nonsteroidal anti-inflammatory drugs and ectodomain shedding of the amyloid precursor protein.
BACKGROUND
Epidemiological studies have suggested that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). Several mechanisms have been proposed to explain these findings including increased shedding of the soluble ectodomain of the amyloid precursor protein (sAPP), which functions as a neurotrophic and neuroprotective factor in vitroand in vivo.


OBJECTIVE
To clarify whether NSAIDs consistently stimulate sAPP secretion.


METHODS
293-EBNA cells with stable overexpression of an APP-alkaline phosphatase fusion protein (APP-AP), SH-SY5Y and PC12 cells or primary telencephalic chicken neurons were treated with ibuprofen or indomethacin. APP shedding was then determined by measuring AP activity in conditioned media, Western blot analysis with antibodies against total sAPP or specific for sAPP-alpha, or in a pulse-chase paradigm.


RESULTS
AP activity in conditioned media was not increased after NSAID treatment of 293-EBNA cells whereas it was elevated by phorbol ester. Surprisingly, ibuprofen or indomethacin treatment of SH-SY5Y and PC12 cells expressing endogenous APP did not cause changes in sAPP or sAPP-alpha secretion or downregulation of cellular APP. These findings were further corroborated in primary chicken neuronal cultures.


CONCLUSIONS
Using various experimental settings, we were unable to confirm sAPP or sAPP-alpha stimulation with the NSAIDs ibuprofen and indomethacin in transfected and nontransfected cells of neuronal and nonneuronal origin. Importantly, these findings seem to rule out chronic sAPP stimulation as an alternative mechanism of NSAID action in AD.
Leuchtenberger
Stefanie
S
Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
Maler
Juan
J
Czirr
Eva
E
Ness
Julia
J
Lichtenthaler
Stefan F
SF
Esselmann
Hermann
H
Pietrzik
Claus U
CU
Wiltfang
Jens
J
Weggen
Sascha
S
D000469:Alkaline Phosphatase / Q000009:adverse effects; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D009447:Neuroblastoma; D016716:PC12 Cells / Q000187:drug effects; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000469:Alkaline Phosphatase; D013755:Tetradecanoylphorbol Acetate; D007052:Ibuprofen; D007213:Indomethacin