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

Beta-amyloid peptides (A beta) 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 A beta are anti-angiogenic both in vitro and in vivo. However, the mechanism of the anti-angiogenic activity of A beta peptides is unclear. In this study, we examined the effects of A beta 1-42 on vascular endothelial growth factor receptor 2 (VEGFR-2) signaling, which plays a key role in angiogenesis. A beta 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 A beta in a capillary network assay. A beta 1-42 also blocked VEGF-induced tyrosine phosphorylation of VEGFR-2 in two types of primary endothelial cells, suggesting an antagonistic action of A beta toward VEGFR-2 signaling in cells. Moreover, A beta 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 A beta can bind VEGFR-2 both in vitro and in vivo. Altogether, our data suggest that A beta acts as an antagonist of VEGFR-2 and provide a mechanism explaining the anti-angiogenic activity of A beta peptides.