Molecular membrane interactions of a phospholipid metabolite. Implications for Alzheimer's disease pathophysiology

Alzheimer's disease is characterized by changes in phospholipid metabolism leading to a perturbation in the levels of phosphomonoesters, including L-Phosphoserine (L-PS). These early changes in lipid metabolism may result in a defect in membrane bilayer structure, leading to increased rates of beta-amyloid formation. To investigate the effect of L-PS on membrane lipid bilayers, small angle x-ray diffraction and high resolution differential scanning calorimetry (DSC) approaches were used with liposomes composed of lecithin and cholesterol. A one-dimensional electron density profile of a control dimyristoyl phosphatidylcholine (DMPC)/cholesterol lipid bilayer with a unit cell dimension of 52 A at 37 degrees C was generated from the x-ray diffraction data. Following incubation with 2.0 mM L-PS, a broad decrease in electron density +/- 4.12A from the lipid bilayer center was observed concomitant with an increase in the width of the phospholipid headgroup electron density and a 3A reduction in lipid bilayer width. The interactions of L-PS with DMPC lipid bilayers were concentration-dependent, highly affected by cholesterol content and reproduced in egg phosphatidylcholine/cholesterol liposomes. DSC analysis showed that millimolar (1.0-5.0 mM) L-PS levels decreased the phase transition cooperative unit size of DMPC liposomes in a highly concentration-dependent manner which was significantly greater in preparations containing 10 mol% cholesterol. These data provide direct evidence that phosphomonoester levels modulate the biophysical properties of the membrane lipid bilayer which may, in turn, lead to altered structure/function relationships in AD.