Contribution of gamma-secretase to calcium-mediated cell death

Neurosci Lett. 2010 Jan 29;469(3):425-8. doi: 10.1016/j.neulet.2009.12.043. Epub 2009 Dec 23.


Presenilins are the catalytic subunit of the large gamma-secretase complex, that promotes intramembranous proteolysis of the beta-amyloid precursor protein (APP), resulting in the production of beta-amyloid (A beta). Mutant presenilin causes early-onset familial Alzheimer's disease (FAD), is related to abnormal Ca(2+) signaling, and render cells vulnerable to cell death. In the present study, we demonstrated that Ca(2+)-mediated cell death is functionally associated with gamma-secretase activity. We found that gamma-secretase activity was elevated during Ca(2+)-mediated cell death. Using selective gamma-secretase inhibitors, we examined the role of gamma-secretase in cell death triggered by increased intracellular Ca(2+). Indeed, treatment with the selective gamma-secretase inhibitors, compound E, DAPT, or L-685.458 significantly decreased Ca(2+)-triggered cell death with that of the controls, but did not affect staurosporin or tunicamycin-mediated cell death. These results implicate the role of gamma-secretase activity in Ca(2+)-mediated cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Calcium / metabolism*
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / enzymology
  • Hippocampus / physiology
  • Intracellular Space / drug effects
  • Intracellular Space / enzymology
  • Intracellular Space / physiology
  • Neurons / drug effects
  • Neurons / enzymology*
  • Neurons / physiology*
  • Rats
  • Rats, Sprague-Dawley


  • Enzyme Inhibitors
  • Amyloid Precursor Protein Secretases
  • Calcium