O2–03–05: Gleevec increases levels of the APP intracellular domain (AICD) and the Abeta degrading enzyme neprilysin
Year: 2006
Type: article
Abstract: β–Amyloid (Aβ) deposition is a major pathological hallmark of Alzheimer's disease. Therapeutic approaches aimed at lowering the amyloid burden include the ινηιβιτι°ν of Aβ generation by γ–secretase inhibiton. Gleevec, a tyrosine kinase inhibitor, has been shown to lower Aβ secretion without influencing cleavage of the Notch receptor. It is thus discussed as an APP–selective γ–secretase inhibitor and basis for the development of novel therapies for Alzheimer's disease (Netzer et al.; PNAS 100: 12444–49; 2003). To investigate the mechanism by which Gleevec lowers secreted Aβ. H4 cells, which stably overexpress APP751, were treated with different Gleevec concentrations and secreted Aβ was determined by sandwich ELISA. Cell viability was measured by MTS assay. The amount of APP, APP–C–terminal fragments, secreted APPs–alpha and neprilysin was analyzed by gel electrophoresis and immunoblot analysis. We further determined the effect of Gleevec on γ–secretase activity in vitro. Here we report that Gleevec decreases Aβ by a mechanism distinct from γ–secretase inhibition. Gleevec does not influence γ–secretase cleavage in vitro, however in cell lines it leads to a dose dependent increase in AICD and a decrease in secreted Aβ. Concomitant with the AICD increase Gleevec treatment leads to enhanced levels of the Aβ degrading enzyme neprilysin, which has been described as a target gene of AICD (Pardossi–Piquard et al., Neuron 46:541–554; 2005). Gleevec does not seem to inhibit γ–secretase cleavage of APP. The observed increase in AICD after Gleevec treatment might lead to enhanced AICD signaling which then induces neprilysin expression. The Gleevec–mediated decrease in Aβ may thus be due to enhanced degradation by neprilysin. Studying this signaling mechanism further may lead to discover new targets for Aβ lowering drugs.
Source: Alzheimer s & Dementia
Authors: Ellen Kilger, Yvonne S. Eisele, Matthias Baumann, Bert Klebl, Mathias Jucker
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2916286197