Membrane fusogenic activity of the Alzheimer's peptide A beta(1-42) demonstrated by small-angle neutron scattering.
Amyloid-beta peptide (A beta) is considered a triggering agent of Alzheimer's disease. In relation to a therapeutic treatment of the disease, the interaction of A beta with the cell membrane has to be elucidated at the molecular level to understand its mechanism of action. In previous works, we had ascertained by neutron diffraction on stacked lipid multilayers that a toxic fragment of A beta is able to penetrate and perturb the lipid bilayer. Here, the influence of A beta(1-42), the most abundant A beta form in senile plaques, on unilamellar lipid vesicles of phospholipids is investigated by small-angle neutron scattering. We have used the recently proposed separated form factor method to fit the data and to obtain information about the vesicle diameter and structure of the lipid bilayer and its change upon peptide administration. The lipid membrane parameters were obtained with different models of the bilayer profile. As a result, we obtained an increase in the vesicle radii, indicating vesicle fusion. This effect was particularly enhanced at pH 7.0 and at a high peptide/lipid ratio. At the same time, a thinning of the lipid bilayer occurred. A fusogenic activity of the peptide may have very important consequences and may contribute to cytotoxicity by destabilizing the cell membrane. The perturbation of the bilayer structure suggests a strong interaction and/or insertion of the peptide into the membrane, although its localization remains beyond the limit of the experimental resolution.
Dante
Silvia
S
BENSC, Hahn-Meitner-Institut, Glienicker Strasse 100, D-14109 Berlin, Germany. silvia.dante@hmi.de
Hauss
Thomas
T
Brandt
Astrid
A
Dencher
Norbert A
NA
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008561:Membrane Fusion; D008954:Models, Biological; D033363:Neutron Diffraction; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D053838:Scattering, Small Angle; D012995:Solubility / Q000187:drug effects; D014269:Trifluoroacetic Acid / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D008081:Liposomes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D014269:Trifluoroacetic Acid