Membrane interactions of a phosphomonoester elevated early in Alzheimer's disease.
Phosphoserine (L-PS) is among several phosphomonoesters found to be elevated in autopsied Alzheimer's 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 degrees C was generated from the X-ray diffraction data. Following incubation with 2.0 mM L-PS, a broad decrease in electron density +/- 4-12 A from the lipid bilayer center was observed concomitant with an increase in the width of the phospholipid headgroup electron density and a 3 A 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.
Biomolecular Structure Analysis Center, University of Connecticut Health Center, Farmington 06030-2017, USA.
R P
RP
Mason
M W
MW
Trumbore
J W
JW
Pettegrew
D000544:Alzheimer Disease / Q000378:metabolism*; D055592:Biophysical Phenomena; D001703:Biophysics; D002152:Calorimetry, Differential Scanning; D002784:Cholesterol / Q000378:metabolism; D004134:Dimyristoylphosphatidylcholine / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism*; D008081:Liposomes / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism*; D014961:X-Ray Diffraction
D008051:Lipid Bilayers; D008081:Liposomes; D010768:Phosphoserine; D002784:Cholesterol; D004134:Dimyristoylphosphatidylcholine