Alzheimer's beta-amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR-2

J Neurochem. 2010 Jan;112(1):66-76. doi: 10.1111/j.1471-4159.2009.06426.x. Epub 2009 Oct 10.

Abstract

Beta-amyloid peptides (Abeta) are the major constituents of senile plaques and cerebrovascular deposits in the brains of Alzheimer's disease patients. We have shown previously that soluble forms of Abeta are anti-angiogenic both in vitro and in vivo. However, the mechanism of the anti-angiogenic activity of Abeta peptides is unclear. In this study, we examined the effects of Abeta1-42 on vascular endothelial growth factor receptor 2 (VEGFR-2) signaling, which plays a key role in angiogenesis. Abeta inhibited VEGF-induced migration of endothelial cells, as well as VEGF-induced permeability of an in vitro model of the blood brain barrier. Consistently, exogenous VEGF dose-dependently antagonized the anti-angiogenic activity of Abeta in a capillary network assay. Abeta1-42 also blocked VEGF-induced tyrosine phosphorylation of VEGFR-2 in two types of primary endothelial cells, suggesting an antagonistic action of Abeta toward VEGFR-2 signaling in cells. Moreover, Abeta was able to directly interact with the extracellular domain of VEGFR-2 and to compete with the binding of VEGF to its receptor in a cell-free assay. Co-immunoprecipitation experiments confirmed that Abeta can bind VEGFR-2 both in vitro and in vivo. Altogether, our data suggest that Abeta acts as an antagonist of VEGFR-2 and provide a mechanism explaining the anti-angiogenic activity of Abeta peptides.

Publication types

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

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / physiology*
  • Angiogenesis Inhibitors / antagonists & inhibitors
  • Angiogenesis Inhibitors / physiology
  • Animals
  • Cell Movement / physiology
  • Cells, Cultured
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Humans
  • Mice
  • Mice, Transgenic
  • Peptide Fragments / metabolism
  • Peptide Fragments / physiology*
  • Protein Binding / physiology
  • Signal Transduction / physiology*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / physiology*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • Amyloid beta-Peptides
  • Angiogenesis Inhibitors
  • Peptide Fragments
  • Vascular Endothelial Growth Factor A
  • amyloid beta-protein (1-42)
  • Vascular Endothelial Growth Factor Receptor-2