ZFIN ID: ZDB-PUB-020716-21
A {gamma}-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish
Geling, A., Steiner, H., Willem, M., Bally-Cuif, L., and Haass, C.
Date: 2002
Source: EMBO reports   3(7): 688-694 (Journal)
Registered Authors: Bally-Cuif, Laure, Geling, Andrea
Keywords: none
MeSH Terms:
  • Alzheimer Disease/metabolism
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor/metabolism
  • Animals
  • Aspartic Acid Endopeptidases
  • Body Patterning/drug effects
  • Cell Line
  • Endopeptidases/chemistry
  • Endopeptidases/metabolism*
  • Enzyme Inhibitors/pharmacology*
  • Humans
  • In Situ Hybridization
  • Membrane Proteins/metabolism*
  • Microinjections
  • Phenotype
  • Presenilin-1
  • RNA, Messenger/metabolism
  • Receptors, Notch
  • Signal Transduction/drug effects
  • Signal Transduction/physiology*
  • Triglycerides/pharmacology*
  • Zebrafish/embryology
  • Zebrafish/physiology*
  • gamma-Aminobutyric Acid/analogs & derivatives*
  • gamma-Aminobutyric Acid/pharmacology*
PubMed: 12101103 Full text @ EMBO Rep.
Inhibition of amyloid beta-peptide (Abeta) production by blocking gamma-secretase activity is at present one of the most promising therapeutic strategies to slow progression of Alzheimer's disease pathology. gamma-secretase inhibitors apparently block Abeta generation via interference with presenilin (PS) function. Besides being an essential component of the gamma-secretase complex, PS itself may be an aspartyl protease with gamma-secretase activity, which is not only required for Abeta production but also for a similar proteolytic process involved in Notch signaling. Here we demonstrate that treatment of zebrafish embryos with a known gamma-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 gamma-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 Abeta production, but not Notch signaling, under in vivo conditions.