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MBC in Press, published online ahead of print July 11, 2007
Mol. Biol. Cell 10.1091/mbc.E07-01-0035

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Submitted on January 16, 2007
Revised on May 21, 2007
Accepted on June 28, 2007

Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain (AICD) and of the A{beta}-degrading Enzyme Neprilysin

Yvonne S. Eisele,* Matthias Baumann,{dagger}{ddagger} Bert Klebl,{dagger}{ddagger} Christina Nordhammer,* Mathias Jucker,* and Ellen Kilger*

*Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany; {dagger}Axxima Pharmaceuticals AG, D-81377 Munich, Germany

Monitoring Editor: Jonathan Weissman

Amyloid-{beta} (A{beta}) deposition is a major pathological hallmark of Alzheimer’s disease. Gleevec, a known tyrosine kinase inhibitor, has been shown to lower A{beta} secretion and is considered a potential basis for novel therapies for Alzheimer’s disease. Here we show that Gleevec decreases A{beta} levels without the inhibition of Notch cleavage by a mechanism distinct from {gamma}-secretase inhibition. Gleevec does not influence {gamma}-secretase activity in vitro, however treatment of cell lines leads to a dose-dependent increase in the APP intracellular domain (AICD), while secreted A{beta} is decreased. This effect is observed even in presence of a potent {gamma}-secretase inhibitor, suggesting that Gleevec does not activate AICD generation but instead may slow down AICD turnover. Concomitant with the increase in AICD, Gleevec leads to elevated mRNA and protein levels of the A{beta}-degrading enzyme neprilysin, a potential target gene of AICD-regulated transcription. Thus the Gleevec mediated-increase in neprilysin expression may involve enhanced AICD signaling. The finding that Gleevec elevates neprilysin levels suggests that its A{beta} lowering effect may be caused by increased A{beta}-degradation.

{ddagger}Present address: GPC Biotech AG, Martinsried, Germany.

Address correspondence to: Ellen Kilger (ellen.kilger{at}uni-tuebingen.de)




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