The amyloid protein precursor (APP) was incorporated into liposomes or phospholipid monolayers. APP insertion into liposomes required neutral lipids, such as L-a-phosphatidylcholine, in the target membrane. It was prevented in vesicles containing L-a-phosphatidylserine. The insertion was enhanced in acidic solutions, suggesting that it is modulated by specific charge/charge interactions. Surfaceactive properties and behaviour of APP were characterized during insertion of the protein in monomolecular films of L-a-phosphatidylcholine, L-a-phosphatidylethanolamine or L-a-phosphatidylserine. The presence of the lipid film enhanced the rate of adsorption of the protein at the interface, and the increase in surface pressure was consistent with APP penetrating the lipid film. The adsorption of APP on the lipid monolayers displayed a significant head group dependency, suggesting that the changes in surface pressure produced by the protein were probably affected by electrostatic interactions with the lipid layers. Our results indicate that the penetration of the protein into the lipid monolayer is also influenced by the hydrophobic interactions between APP and the lipid. CD spectra showed that a large proportion of the a-helical secondary structure of APP remained preserved over the pH or ionic strength ranges used. Our findings suggest that APP/membrane interactions are mediated by the lipid composition and depend on both electrostatic and hydrophobic effects, and that the variations observed are not due to major secondary structural changes in APP. These observations may be related to the partitioning of APP into membrane microdomains.
APP (amyloid precursor protein), together with Chol (cholesterol) and ApoE (apolipoprotein E), has been linked to Alzheimer's disease. We have examined the hypothesis that interaction of APP with the lipid membranes is modulated by Chol and ApoE. Insertion of APP into lipid monolayers was first evidenced as an increase in the surface pressure. APP injected into a subphase induced a substantial increase in the surface pressure of monolayers prepared from PC (L-alpha-phosphatidylcholine), Chol, SPM (sphingomyelin) and PS (L-alpha-phosphatidylserine), the major lipids present in the plasma membranes of brain cells. At a given initial pressure, the insertion of APP into expanded monolayers is higher than that in condensed monolayers, in the order Chol>PC>SPM>PS. The membrane insertion capacity of APP was also measured from surface pressure versus area (pi-A) isotherms of APP-lipid monolayers. The increase in the mean area per molecule in protein-lipid monolayers, in the order PC>Chol>PS>SPM, provides further evidence for protein-lipid interactions. These interactions occurred at optimum salt levels and optimum pH values close to physiological conditions (150 mM NaCl and pH 7.4). In addition, ApoE4 affected the insertion of APP into lipid films. APP-ApoE complexes showed a decreased ability to penetrate lipid monolayers at a constant area. APP-ApoE complexes expanded the pi-A isotherm of a Chol monolayer to a lesser extent than APP alone. These experiments demonstrate the roles of Chol and ApoE in the modulation of membrane insertion of APP.
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