J. Neurochem. (2010) 112, 66–76.
Beta-amyloid peptides (Aβ) 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 Aβ are anti-angiogenic both in vitro and in vivo. However, the mechanism of the anti-angiogenic activity of Aβ peptides is unclear. In this study, we examined the effects of Aβ1–42 on vascular endothelial growth factor receptor 2 (VEGFR-2) signaling, which plays a key role in angiogenesis. Aβ 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 Aβ in a capillary network assay. Aβ1–42 also blocked VEGF-induced tyrosine phosphorylation of VEGFR-2 in two types of primary endothelial cells, suggesting an antagonistic action of Aβ toward VEGFR-2 signaling in cells. Moreover, Aβ 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 Aβ can bind VEGFR-2 both in vitro and in vivo. Altogether, our data suggest that Aβ acts as an antagonist of VEGFR-2 and provide a mechanism explaining the anti-angiogenic activity of Aβ peptides.