beta-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 th e development of late-onset and sporadic forms of Alzheimer's disease, alth ough its exact role remains unclear. We previously demonstrated that beta-a myloid peptide (A beta) displays membrane-destabilizing properties and that only apoE2 and E3 isoforms inhibit these properties. In this study, we cle arly demonstrate that the carboxy-terminal lipid-binding domain of apoE (e. g., residues 200-299) is responsible for the A beta-binding activity of apo E and that this interaction involves pairs of apoE amphipathic alpha-helice s. 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/a poE complexes resistant to sodium dodecyl sulfate-polyacrylamide gel electr ophoresis. On the contrary, the amino-terminal receptor-binding domain of a poE (e.g,, residues 129-169) is not able to form stable complexes with A be ta. These data extend our understanding of human apoE-dependent binding of A beta by involving the C-terminal domain of apoE in the efficient formatio n of apoE/A beta complex.