A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish |
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Authors: | Geling Andrea Steiner Harald Willem Michael Bally-Cuif Laure Haass Christian |
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Affiliation: | Zebrafish Neurogenetics Junior Research Group, Institute for Virology, Technical University Munich, Trogerstrasse, Germany. |
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Abstract: | Inhibition of amyloid β-peptide (Aβ) production by blocking γ-secretase activity is at present one of the most promising therapeutic strategies to slow progression of Alzheimer’s disease pathology. γ-secretase inhibitors apparently block Aβ generation via interference with presenilin (PS) function. Besides being an essential component of the γ-secretase complex, PS itself may be an aspartyl protease with γ-secretase activity, which is not only required for Aβ production but also for a similar proteolytic process involved in Notch signaling. Here we demonstrate that treatment of zebrafish embryos with a known γ-secretase inhibitor affects embryonic development in a manner indistinguishable from Notch signaling deficiencies at morphological, molecular and biochemical levels. This indicates severe side-effects of γ-secretase inhibitors in any Notch-dependent cell fate decision and demonstrates that the zebrafish is an ideal vertebrate system to validate compounds that selectively affect Aβ production, but not Notch signaling, under in vivo conditions. |
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