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Vol. 18, Issue 9, 3591-3600, September 2007

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Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-–degrading Enzyme Neprilysin

Yvonne S. Eisele^*, Matthias Baumann^,, Bert Klebl^,, Christina Nordhammer^*, Mathias Jucker^*, and Ellen Kilger^*

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

Submitted January 16, 2007; Revised May 21, 2007; Accepted June 28, 2007
Monitoring Editor: Jonathan Weissman

Amyloid- (A) deposition is a major pathological hallmark of Alzheimer's disease. Gleevec, a known tyrosine kinase inhibitor, has been shown to lower A secretion, and it is considered a potential basis for novel therapies for Alzheimer's disease. Here, we show that Gleevec decreases A levels without the inhibition of Notch cleavage by a mechanism distinct from -secretase inhibition. Gleevec does not influence -secretase activity in vitro; however, treatment of cell lines leads to a dose-dependent increase in the amyloid precursor protein intracellular domain (AICD), whereas secreted A is decreased. This effect is observed even in presence of a potent -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-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-lowering effect may be caused by increased A-degradation.

Present address: GPC Biotech AG, 82152 Martinsried, Germany.

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

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