A γ‐secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish
Open Access
- 1 July 2002
- journal article
- research article
- Published by Springer Nature in EMBO Reports
- Vol. 3 (7) , 688-694
- https://doi.org/10.1093/embo-reports/kvf124
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.Keywords
This publication has 61 references indexed in Scilit:
- APP Processing and Synaptic Plasticity in Presenilin-1 Conditional Knockout MiceNeuron, 2001
- A Portrait of Alzheimer Secretases--New Features and Familiar FacesScience, 2001
- The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formationNature Neuroscience, 2001
- Aβ-Generating EnzymesNeuron, 2000
- Aspartate Mutations in Presenilin and γ‐Secretase Inhibitors Both Impair Notch1 Proteolysis and Nuclear Translocation with Relative Preservation of Notch1 SignalingJournal of Neurochemistry, 2000
- Zebrafish (Danio rerio) Presenilin Promotes Aberrant Amyloid β-Peptide Production and Requires a Critical Aspartate Residue for Its Function in AmyloidogenesisBiochemistry, 1999
- Amyloid β-Protein FibrillogenesisJournal of Biological Chemistry, 1997
- Improved electrophoretic separation and immunoblotting of beta‐amyloid (Aβ) peptides 1–40, 1–42, and 1–43Electrophoresis, 1997
- Stages of embryonic development of the zebrafishDevelopmental Dynamics, 1995
- Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein productionNature, 1992