Amyloid-beta (Abeta) deposition is a major pathological hallmark of Alzheimer's disease. Gleevec, a known tyrosine kinase inhibitor, has been shown to lower Abeta secretion, and it is considered a potential basis for novel therapies for Alzheimer's disease. Here, we show that Gleevec decreases Abeta 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 amyloid precursor protein intracellular domain (AICD), whereas secreted Abeta 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 Abeta-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 Abeta-lowering effect may be caused by increased Abeta-degradation.