Specific interaction of VEGF165 with beta-amyloid, and its protective effect on beta-amyloid-induced neurotoxicity.
beta-amyloid (Abeta) 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 Abeta and is accumulated in the senile plaques of AD patients' brains. Here we show that Abeta interacts with VEGF(165) isoform, but not with VEGF(121). Abeta binds to the heparin-binding domain (HBD) of VEGF(165) with similar affinity as that of intact VEGF(165). Abeta 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 Abeta. Although Abeta binds to heparin-binding sequence of VEGF, it does not bind to other heparin-binding growth factors except midkine. Thus it seems that Abeta recognizes unique structural features of VEGF HBD. VEGF(165) prevents aggregation of Abeta through its HBD. We localized the core VEGF binding site of Abeta at around 26-35 region of the peptide. VEGF(165) and HBD protect PC12 cells from the Abeta-induced cytotoxicity. The mechanism of protection appears to be inhibition of both Abeta-induced formation of reactive oxygen species and Abeta aggregation.
Yang
Seung-Pil
SP
Department of Life Science, Division of Molecular and Life Sciences, and Postech Biotech Center, Pohang University of Science and Technology, Pohang, Korea.
Kwon
Byoung-Oh
BO
Gho
Yong Song
YS
Chae
Chi-Bom
CB
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016716:PC12 Cells / Q000187:drug effects; D010446:Peptide Fragments; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance / Q000379:methods; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D016207:Cytokines; D010446:Peptide Fragments; D020033:Protein Isoforms; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C075222:amyloid beta-protein (1-42); C066845:pleiotrophin