β-amyloid peptide interacts specifically with the carboxy-terminal domain of human apolipoprotein E:: Relevance to Alzheimer's disease

Growing evidence indicates the involvement of apolipoprotein E (apoE) in the development of late-onset and sporadic forms of Alzheimer's disease, although its exact role remains unclear. We previously demonstrated that beta-amyloid peptide (A beta) displays membrane-destabilizing properties and that only apoE2 and E3 isoforms inhibit these properties. In this study, we clearly demonstrate that the carboxy-terminal lipid-binding domain of apoE (e.g., residues 200-299) is responsible for the A beta-binding activity of apoE and that this interaction involves pairs of apoE amphipathic alpha-helices. We further demonstrate that A beta is able to inhibit the association of the C-terminal domain of apoE with lipids due to the formation of A beta/apoE complexes resistant to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. On the contrary, the amino-terminal receptor-binding domain of apoE (e.g,, residues 129-169) is not able to form stable complexes with A beta. These data extend our understanding of human apoE-dependent binding of A beta by involving the C-terminal domain of apoE in the efficient formation of apoE/A beta complex.