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.