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-α-phosphatidylcholine), Chol, SPM (sphingomyelin) and PS (L-α-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 (π–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 π–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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