β-Amyloid Peptide Interacts Specifically with the Carboxyl-Terminal Domain of Human Apolipoprotein E

Relevance to Alzheimer's Disease

Authors


  • Abbreviations used : Aβ, β-amyloid peptide ; AD, Alzheimer's disease ; apoA-I, apolipoprotein A-I ; apoE, apolipoprotein E ; CD, circular dichroism ; DMPC, dimyristoylphosphatidylcholine ; E/M, pyrene excimer/monomer ratio ; GdnHCl, guanidine HCl ; HFP, hexafluoro-2-propanol ; PC, l-α-phosphatidylcholine ; PE, l-α-phosphatidylethanolamine ; PS, l-α-phosphatidyl-l-serine ; Pyr-PC, 1-palmitoyl-2-pyrene(14)-phosphatidylcholine ; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis ; SIV, simian immunodeficiency virus ; SM, sphingomyelin ; SUV, small unilamellar vesicle ; TFE, 2,2,2-trifluoroethanol.

Address correspondence and reprint requests to Dr. T. Pillot at CJF INSERM 9508, Institut des Cordeliers, 15 Rue de l'Ecole de Médecine, 75006 Paris, France.

Abstract

Abstract : 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 β-amyloid peptide (Aβ) 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 Aβ-binding activity of apoE and that this interaction involves pairs of apoE amphipathic α-helices. We further demonstrate that Aβ is able to inhibit the association of the C-terminal domain of apoE with lipids due to the formation of Aβ/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 Aβ. These data extend our understanding of human apoE-dependent binding of Aβ by involving the C-terminal domain of apoE in the efficient formation of apoE/Aβ complex.

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