Alzheimer's beta-amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR-2.
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.
Patel
Nikunj S
NS
Roskamp Institute, Sarasota, Florida, USA. npatel@scripps.edu
Mathura
Venkatarajan S
VS
Bachmeier
Corbin
C
Beaulieu-Abdelahad
David
D
Laporte
Vincent
V
Weeks
Ophelia
O
Mullan
Michael
M
Paris
Daniel
D
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000502:physiology*; D020533:Angiogenesis Inhibitors / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; C075222:amyloid beta-protein (1-42); D040301:Vascular Endothelial Growth Factor Receptor-2