Protection against amyloid beta-peptide (1-42)-induced loss of phospholipid asymmetry in synaptosomal membranes by tricyclodecan-9-xanthogenate (D609) and ferulic acid ethyl ester: implications for Alzheimer's disease.
Amyloid-beta (1-42) [Abeta (1-42)] deposition in the brain is a hallmark of Alzheimer's disease (AD) and has been shown to induce apoptosis and disrupt cellular ion homeostasis. Abeta (1-42) induces membrane lipid peroxidation, and 4-hydroxynonenal (HNE) and 2-propenal (acrolein) are the two reactive products of lipid peroxidation, which structurally modify proteins by covalent interaction and inhibit enzyme function. Phosphatidylserine (PS), an aminophospholipid, is sequestered in the inner leaflet of the plasma membrane in nonstimulated cells. An early signal of synaptosomal apoptosis is the loss of phospholipid asymmetry and the appearance of phosphatidylserine in the outer leaflet of the membrane. The ATP-requiring enzyme, flippase, maintains phospholipid asymmetry of PS. Here, we have investigated the inactivation of the transmembrane enzyme aminophospholipid-translocase (or flippase) by Abeta (1-42). Flippase activity depends on a critical cysteine residue, a putative site of covalent modification by the Abeta (1-42)-induced lipid peroxidation products, HNE or acrolein. The present study is aimed to investigate the protective effects of tricyclodecan-9-xanthogenate (D609) and ferulic acid ethyl ester (FAEE) on Abeta (1-42) induced modulation in phospholipid asymmetry in the synaptosomal membranes. Pretreatment of synaptosomes with D609 and FAEE significantly protected Abeta (1-42)-induced loss of phospholipid asymmetry in synaptosomal membranes. Our results suggest that D609 and FAEE exert protective effects against Abeta (1-42) induced apoptosis. The increase in intracellular Ca(2+) might not be the sole cause for the loss of flippase activity. Rather, other mechanisms that could modulate the function of flippase might be important in the modulation of phospholipid asymmetry. The results of this study are discussed with relevance to neuronal loss in the AD brain.
Mohmmad Abdul
Hafiz
H
Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA.
Butterfield
D Allan
DA
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000737:chemistry; D003373:Coumaric Acids / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005849:Gerbillinae; D015227:Lipid Peroxidation / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D009636:Norbornanes; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D049294:Phospholipid Transfer Proteins / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D020011:Protective Agents; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D013859:Thiocarbamates; D013871:Thiones / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D001952:Bridged-Ring Compounds; D003373:Coumaric Acids; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009636:Norbornanes; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; D020011:Protective Agents; D013859:Thiocarbamates; D013871:Thiones; C075222:amyloid beta-protein (1-42); C046498:tricyclodecane-9-yl-xanthogenate; C004999:ferulic acid