A Gamma-Secretase Inhibitor Blocks Notch Signaling in Vivo and Causes a Severe Neurogenic Phenotype in Zebrafish

EMBO Rep. 2002 Jul;3(7):688-94. doi: 10.1093/embo-reports/kvf124.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

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*

Substances

  • Amyloid beta-Protein Precursor
  • Enzyme Inhibitors
  • Membrane Proteins
  • PSEN1 protein, human
  • Presenilin-1
  • RNA, Messenger
  • Receptors, Notch
  • Triglycerides
  • gamma-Aminobutyric Acid
  • 1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human