Specific interaction of VEGF165 with beta-amyloid, and its protective effect on beta-amyloid-induced neurotoxicity.

Abstract

beta-amyloid (A beta) is a major component of senile plaques that is commonly found in the brain of Alzheimer's disease (AD) patient. In the previous report, we showed that an important angiogenic factor, vascular endothelial growth factor (VEGF) interacts with A beta and is accumulated in the senile plaques of AD patients' brains. Here we show that A beta interacts with VEGF(165) isoform, but not with VEGF(121). A beta binds to the heparin-binding domain (HBD) of VEGF(165) with similar affinity as that of intact VEGF(165). A beta binds mostly to the C-terminal subdomain of HBD, but with greatly reduced affinity than HBD. Therefore, the full length of HBD appears to be required for maximal binding of A beta. Although A beta binds to heparin-binding sequence of VEGF, it does not bind to other heparin-binding growth factors except midkine. Thus it seems that A beta recognizes unique structural features of VEGF HBD. VEGF(165) prevents aggregation of A beta through its HBD. We localized the core VEGF binding site of Ab at around 26-35 region of the peptide. VEGF(165) and HBD protect PC12 cells from the A beta-induced cytotoxicity. The mechanism of protection appears to be inhibition of both A beta-induced formation of reactive oxygen species and A beta aggregation.