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Activation of amyloid precursor protein processing by growth factors is dependent on Ras GTPase activity

Loredana Amigoni1, Michela Ceriani, Fiorella Belotti

  • 1Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza Della Scienza 2, 20126, Milan, Italy.

Neurochemical Research
|December 17, 2010
PubMed

Insights

Ras GTPase promotes amyloid precursor protein (APP) cleavage, a key step in β-amyloid peptide generation. This Ras-dependent process involves γ-secretase activity and is activated by growth factors like EGF and PDGF.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • β-amyloid peptide (Aβ) is central to Alzheimer's disease pathogenesis.
  • The precise mechanisms regulating amyloid precursor protein (APP) proteolysis remain unclear.
  • Understanding APP cleavage is crucial for developing therapeutic strategies.

Purpose of the Study:

  • To investigate signaling pathways involved in APP cleavage.
  • To identify specific GTPases that regulate APP proteolysis.
  • To elucidate the role of growth factor signaling in APP processing.

Main Methods:

  • Utilized a HeLa cell line stably expressing an APP-Gal4 fusion protein reporter.
  • Employed a luciferase reporter gene assay to quantify APP cleavage events.
  • Stimulated cells with epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and overexpressed epidermal growth factor receptor (EGFR).

Main Results:

  • Demonstrated that Ras GTPase, but not Ral or Rap, significantly promotes APP-Gal4 cleavage.
  • Observed increased APP proteolysis in cells stimulated with EGF or PDGF, or overexpressing EGFR.
  • Confirmed that this enhanced APP cleavage is Ras-dependent and requires γ-secretase activity, as it was inhibited by DAPT.

Conclusions:

  • Ras GTPase plays a critical role in regulating APP cleavage.
  • Growth factor signaling pathways converge on Ras to modulate APP proteolysis.
  • The findings highlight a novel link between Ras signaling, γ-secretase, and Aβ production.

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