Gamma secretase-activating protein is a substrate for caspase-3: implications for Alzheimer's disease

Biol Psychiatry. 2015 Apr 15;77(8):720-8. doi: 10.1016/j.biopsych.2014.06.003. Epub 2014 Jun 16.


Background: A major feature of Alzheimer's disease (AD) is the accumulation of amyloid-beta (Aβ), whose formation is regulated by the gamma-secretase complex and its activating protein (also known as GSAP). Because GSAP interacts with gamma-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-Aβ therapy. However, despite much interest in this protein, the mechanisms involved in its neurobiology are unknown.

Methods: Postmortem brain tissue samples from AD patients, transgenic mouse models of AD, and neuronal cells were used to investigate the molecular mechanism involved in GSAP formation and subsequent amyloidogenesis.

Results: We identified a caspase-3 processing domain in the GSAP sequence and provide experimental evidence that this caspase is essential for GSAP activation and biogenesis of Aβ peptides. Furthermore, we demonstrated that caspase-3-dependent GSAP formation occurs in brains of individuals with AD and two different mouse models of AD and that the process is biologically relevant because its pharmacological blockade reduces Aβ pathology in vivo.

Conclusions: Our data, by identifying caspase-3 as the endogenous modulator of GSAP and Aβ production, establish caspase-3 as a novel, attractive and viable Aβ-lowering therapeutic target for AD.

Keywords: Alzheimer’s disease; Amyloid beta; Caspase-3; Gamma secretase; Gamma secretase-activating protein; Transgenic mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Caspase 3 / genetics
  • Caspase 3 / metabolism*
  • Cell Line, Tumor
  • Female
  • Frontal Lobe / metabolism*
  • Gene Expression Regulation / genetics
  • Humans
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Transgenic
  • Mutagenesis
  • Mutation
  • Neuroblastoma / pathology
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Transfection


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • GSAP protein, human
  • PSEN1 protein, human
  • Presenilin-1
  • Proteins
  • RNA, Small Interfering
  • Caspase 3