MEMBRANE INTERACTIONS OF A PHOSPHOMONOESTER ELEVATED EARLY IN ALZHEIMERS-DISEASE

Phosphoserine (L-PS) is among several phosphomonoesters found to be el evated in autopsied Alzheimer's disease (AD) brain tissue. To investig ate the molecular interactions of L-PS with membrane lipid bilayers, s mall angle X-ray diffraction and high resolution differential scanning calorimetry (DSC) approaches were used with liposomes composed of lec ithin and cholesterol. A one-dimensional electron density profile of a control dimyristoyl phosphatidylcholine (DMPC)/cholesterol lipid bila yer with a unit cell dimension of 52 Angstrom at 37 degrees C was gene rated from the X-ray diffraction data. Following incubation with 2.0 m M L-PS, a broad decrease in electron density +/-4-12 Angstrom from the lipid bilayer center was observed concomitant with an increase in the width of the phospholipid headgroup electron density and a 3 Angstrom reduction in lipid bilayer width. The interactions of L-PS with DMPC lipid bilayers were concentration-dependent, highly affected by choles terol content and reproduced in egg phosphatidylcholine/cholesterol li posomes. 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 gre ater in preparations containing cholesterol. The endotherm width at ha lf-maximum doubled at 5.0 mM and 1.25 mM L-PS, respectively, for DMPC and DMPC/cholesterol liposomes. These data provide direct evidence tha t elevated phosphomonoester levels modulate the biophysical properties of the membrane lipid bilayer which may, in turn, lead to altered str ucture/function relationships in membranes during AD.