Membrane interactions of a phosphomonoester elevated early in Alzheimerʹs disease

Phosphoserine (L-PS) is among several phosphomonoesters found to be elevated in autopsied Alzheimerʹs disease (AD) brain tissue. To investigate the molecular interactions of L-PS with 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°C was generated from the X-ray diffraction data. Following incubation with 2.0 mM L-PS, a broad decrease in electron density ±4−12 A from the lipid bilayer center was observed concomitant with an increase in the width of the phospholipid headgroup electron density and a 3 Å 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 decrease the phase transition cooperative unit size of DMPC liposomes in a highly concentration-dependent manner which was significantly greater in preparations containing cholesterol. The endotherm width at half-maximum doubled at 5.0 mM and 1.25 mM L-PS, respectively, for DMPC and DMPC/cholesterol liposomes. These data provide direct evidence that elevated phosphomonoester levels modulate the biophysical properties of the membrane lipid bilayer which may, in turn, lead to altered structure/function relationships in membranes during AD.