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Volume 271, Number 46, Issue of November 15, 1996 pp. 28757-28765
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Fusogenic Properties of the C-terminal Domain of the Alzheimer -Amyloid Peptide

(Received for publication, March 25, 1996, and in revised form, July 18, 1996)

Thierry Pillot , Marc Goethals ^¶ , Berlinda Vanloo , Corinne Talussot , Robert Brasseur , Joel Vandekerckhove ^¶ , Maryvonne Rosseneu and Laurence Lins

From the  Laboratory for Lipoprotein Chemistry and the ^¶ Flanders Interuniversity Institute for Biotechnology, Department of Biochemistry, Faculty of Medicine, University Gent, B-9000 Gent, Belgium and the  Centre de Biophysique Moléculaire Numérique, Faculté des Sciences Agronomiques de Gembloux, Gembloux, Belgium

A series of natural peptides and mutants, derived from the Alzheimer -amyloid peptide, was synthesized, and the potential of these peptides to induce fusion of unilamellar lipid vesicles was investigated. These peptide domains were identified by computer modeling and correspond to respectively the C-terminal (e.g. residues 29-40 and 29-42) and a central domain (, , , , , , , , , , , , , , , ) of the -amyloid peptide. The C-terminal peptides are predicted to insert in an oblique way into a lipid membrane through their N-terminal end, while the mutants are either parallel or perpendicular to the lipid bilayer. Peptide-induced vesicle fusion was demonstrated by several techniques, including lipid-mixing and core-mixing assays using pyrene-labeled vesicles. The effect of peptide elongation toward the N-terminal end of the entire -amyloid peptide was also investigated. Peptides corresponding to residues 22-42 and 12-42 were tested using the same techniques. Both the 29-40 and 29-42 -amyloid peptides were able to induce fusion of unilamellar lipid vesicles and calcein leakage, and the amyloid 29-42 peptide was the most potent fusogenic peptide. Neither the two mutants or the 13-28 -amyloid peptide had any fusogenic activity. Circular dichroism measurements showed an increase of the -helical content of the two C-terminal peptides at increasing concentrations of trifluoroethanol, which was accompanied by an increase of the fusogenic potential of the peptides. Our data suggest that the -helical content and the angle of insertion of the peptide into a lipid bilayer are critical for the fusogenic activity of the C-terminal domain of the amyloid peptide. The differences observed between the fusogenic capacity of the amyloid 29-40 and 29-42 peptides might result from differences in the degree of penetration of the peptides into the membrane and the resulting membrane destabilization. The longer peptides, residues 22-42 and 12-42, had decreased, but significant, fusogenic properties associated with perturbation of the membrane permeability. These data suggest that the fusogenic properties of the C-terminal domain of the -amyloid peptide might contribute to the cytotoxicity of the peptide by destabilizing the cell membrane.

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