title: Piracetam inhibits the lipid-destabilising effect of the amyloid peptide Abeta C-terminal fragment.
abstract: Amyloid peptide (Abeta) is a 40/42-residue proteolytic fragment of a precursor protein (APP), implicated in the pathogenesis of Alzheimer's disease. The hypothesis that interactions between Abeta aggregates and neuronal membranes play an important role in toxicity has gained some acceptance. Previously, we showed that the C-terminal domain (e.g. amino acids 29-42) of Abeta induces membrane permeabilisation and fusion, an effect which is related to the appearance of non-bilayer structures. Conformational studies showed that this peptide has properties similar to those of the fusion peptide of viral proteins i.e. a tilted penetration into membranes. Since piracetam interacts with lipids and has beneficial effects on several symptoms of Alzheimer's disease, we investigated in model membranes the ability of piracetam to hinder the destabilising effect of the Abeta 29-42 peptide. Using fluorescence studies and 31P and 2H NMR spectroscopy, we have shown that piracetam was able to significantly decrease the fusogenic and destabilising effect of Abeta 29-42, in a concentration-dependent manner. While the peptide induced lipid disorganisation and subsequent negative curvature at the membrane-water interface, the conformational analysis showed that piracetam, when preincubated with lipids, coats the phospholipid headgroups. Calculations suggest that this prevents appearance of the peptide-induced curvature. In addition, insertion of molecules with an inverted cone shape, like piracetam, into the outer membrane leaflet should make the formation of such structures energetically less favourable and therefore decrease the likelihood of membrane fusion.
authors.affiliation: Unité de Pharmacologie Cellulaire et Moléculaire, Université catholique de Louvain, Brussels, Belgium. mingeot@facm.ucl.ac.be
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Mingeot-Leclercq
authors.forename: Laurence
authors.initials: L
authors.lastname: Lins
authors.forename: Mariam
authors.initials: M
authors.lastname: Bensliman
authors.forename: Annick
authors.initials: A
authors.lastname: Thomas
authors.forename: Françoise
authors.initials: F
authors.lastname: Van Bambeke
authors.forename: Jacques
authors.initials: J
authors.lastname: Peuvot
authors.forename: André
authors.initials: A
authors.lastname: Schanck
authors.forename: Robert
authors.initials: R
authors.lastname: Brasseur
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D005453:Fluorescence; D008027:Light; D050356:Lipid Metabolism; D008081:Liposomes; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D010889:Piracetam / Q000494:pharmacology*; D012542:Scattering, Radiation
chemical_list: D016229:Amyloid beta-Peptides; D005452:Fluoresceins; D008081:Liposomes; D010446:Peptide Fragments; C007740:fluorexon; D010889:Piracetam