Nonsteroidal anti-inflammatory drugs and ectodomain shedding of the amyloid precursor protein

Stefanie Leuchtenberger, Juan Maler, Eva Czirr, Julia Ness, Stefan F. Lichtenthaler, Hermann Esselmann, Claus U. Pietrzik, Jens Wiltfang, Sascha Weggen

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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-α, 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-α 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-α 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.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalNeurodegenerative Diseases
Issue number1-2
StatePublished - Dec 2008
Externally publishedYes


  • Alzheimer's disease
  • Amyloid precursor protein
  • Ectodomain shedding
  • Ibuprofen
  • Indomethacin
  • Nonsteroidal anti-inflammatory drugs


Dive into the research topics of 'Nonsteroidal anti-inflammatory drugs and ectodomain shedding of the amyloid precursor protein'. Together they form a unique fingerprint.

Cite this