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

Abstract

β-amyloid (Aβ) 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 Aβ and is accumulated in the senile plaques of AD patients' brains. Here we show that Aβ interacts with VEGF165 isoform, but not with VEGF121. Aβ binds to the heparin-binding domain (HBD) of VEGF165 with similar affinity as that of intact VEGF165. Aβ 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 Aβ. Although Aβ binds to heparin-binding sequence of VEGF, it does not bind to other heparin-binding growth factors except midkine. Thus it seems that Aβ recognizes unique structural features of VEGF HBD. VEGF165 prevents aggregation of Aβ through its HBD. We localized the core VEGF binding site of Aβ at around 26-35 region of the peptide. VEGF165 and HBD protect PC12 cells from the Aβ-induced cytotoxicity. The mechanism of protection appears to be inhibition of both Aβ-induced formation of reactive oxygen species and Aβ aggregation. © 2005 International Society for Neurochemistry.