In Vivo Manifestation of Notch Related Phenotypes in Zebrafish Treated with Alzheimer's Amyloid Reducing gamma-Secretase Inhibitors

Yang, T., Arslanova, D., Xu, X., Li, Y.M., and Xia, W.
Journal of neurochemistry   113(5): 1200-1209 (Journal)
Registered Authors
Arslanova, Dilya, Xia, Weiming
Alzheimer, amyloid, Notch, secretase, zebrafish
MeSH Terms
  • Alzheimer Disease/drug therapy*
  • Amyloid Precursor Protein Secretases/antagonists & inhibitors*
  • Amyloid beta-Peptides/antagonists & inhibitors
  • Amyloid beta-Peptides/biosynthesis
  • Animals
  • Cells, Cultured
  • Dipeptides/pharmacology
  • Embryo, Nonmammalian
  • Heart Rate/physiology
  • In Situ Hybridization
  • Phenotype
  • Pigmentation/physiology
  • Protease Inhibitors/therapeutic use*
  • Receptors, Notch/physiology*
  • Signal Transduction/drug effects
  • Zebrafish/physiology*
20345767 Full text @ J. Neurochem.
gamma-Secretase is responsible for the final cleavage of amyloid precursor protein to generate the amyloid-beta protein, the major component of plaques in the brains of Alzheimer's disease patients. gamma-Secretase inhibitors (GSI) have been explored for therapeutic inhibition of Abeta generation, but mechanistic toxicity has been documented due to its blockage of gamma-secretase cleavage of several dozens of substrates including Notch. This becomes the primary obstacle for most inhibitors during the preclinical development and the main concern for several compounds in the clinical trials. To predict potential side effects related to Notch signaling, we examined global effect of GSIs in vertebrate animal zebrafish. We have used two potent GSIs (GSI A and GSI 18) with a sub-muM effective concentration for 50% Abeta inhibition (EC50). Zebrafish embryos were treated with GSI A, 18 or a well characterized GSI DAPT, and transparent animals were examined for up to 7 days. GSI A had less abnormal phenotype in zebrafish, compared to GSI 18-treated embryos that displayed curved tails, a loss of pigmentation, and reduced swim bladder and heart rate. To understand mechanistic effect at the molecular level, we examined Notch signaling in these GSI-treated zebrafish. Notch phenotypes were observed in embryos treated with 50 and 10 muM GSI 18, but not with 10 muM GSI A. In accordance, in situ hybridization with a probe against Notch target gene her6 showed a weaker staining in embryos treated with 10 muM GSI 18 than those treated with 10 muM GSI A. In conclusion, phenotypic profile in whole animals offers important information on Notch related pathways and provides prediction of safe compounds during early development stages of therapeutic GSIs.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes