The physical origin of the extremely high thermal stability of tetraether liposomes composed of the polar lipid fraction E (PLFE) from the thermoacidophilic archaebacterium Sulfolobus acidocaldarius has been investigated. The leakage rate of trapped 5, 6-carboxyfluorescein (5(6)CF) and the proton permeability in PLFE liposomes have been measured using fluorescence probe techniques in the temperature range of 25-85 degrees C. The results are compared with those obtained from nonarchaebacterial liposomes. Egg yolk phosphatidylglycerol (eggPG) and PLFE liposomes exhibit similar large negative zeta-potentials (-31 to -34 mV) and low permeability coefficients for 5(6)CF, indicating that membrane surface charge is responsible for the low leakage rate of 5(6)CF in PLFE liposomes. This assertion is confirmed by the observation of an increased leakage rate of 5(6)CF with decreasing membrane surface negative charge via varying the content of egg yolk phosphatidylcholine (eggPC) in eggPC/eggPG binary mixtures. Gel-state dipalmitoylphosphatidylcholine bilayers and PLFE liposomes exhibit similar permeability coefficients for 5(6)CF, suggesting that lipid packing also plays an important role in the low leakage rate of 5(6)CF. PLFE liposomes, especially those approximately 60 nm in diameter, are remarkably thermally stable in regard to proton permeability, which increases by less than 2 x 10(-10) cm/s from 25 to 82 degrees C. The proton permeability comparison of various liposomes reveals that the tight and rigid lipid packing is the major contributor of the extremely low proton permeation in PLFE liposomes; the inositol moiety and the branched methyl groups may also contribute, but to a much lesser extent.
Amyloid β proteins and oxidative stress are believed to have central roles in the development of Alzheimer's disease. Lipid membranes are among the most vulnerable cellular components to oxidative stress, and membranes in susceptible regions of the brain are compositionally distinct from those in other tissues. This review considers the evidence that membranes are either a source of neurotoxic lipid oxidation products or the target of pathogenic processes involving amyloid β proteins that cause permeability changes or ion channel formation. Progress toward a comprehensive theory of Alzheimer's disease pathogenesis is discussed in which lipid membranes assume both roles and promote the conversion of monomeric amyloid β proteins into fibrils, the pathognomonic histopathological lesion of the disease.
Evidence of oxidative stress and the accumulation of fibrillar amyloid  proteins (A) in senile plaques throughout the cerebral cortex are consistent features in the pathology of Alzheimer disease. To define a mechanistic link between these two processes, various aspects of the relationship between oxidative lipid membrane damage and amyloidogenesis were characterized by chemical and physical techniques. Earlier studies of this relationship demonstrated that oxidatively damaged synthetic lipid membranes promoted amyloidogenesis. The studies reported herein specify that 4-hydroxy-2-nonenal (HNE) is produced in both synthetic lipids and human brain lipid extracts by oxidative lipid damage and that it can account for accelerated amyloidogenesis. A promotes the copper-mediated generation of HNE from polyunsaturated lipids, and in turn, HNE covalently modifies the histidine side chains of A. HNE-modified A have an increased affinity for lipid membranes and an increased tendency to aggregate into amyloid fibrils. Thus, the prooxidant activity of A leads to its own covalent modification and to accelerated amyloidogenesis. These results illustrate how lipid membranes may be involved in templating the pathological misfolding of A, and they suggest a possible chemical mechanism linking oxidative stress with amyloid formation. Alzheimer disease (AD)3 is an age-related neurodegenerative disorder characterized by misfolded and aggregated fibrillar amyloid  proteins (A) in the brain. Among the factors associated with the pathogenesis of AD, oxidative stress is one of the most closely scrutinized (1, 2). It has been shown, for example, that the brain in AD has increased susceptibility to oxidative stress (3-5) and that isoprostanes, markers of oxidative stress, are specifically elevated (6 -8). Isoprostanes are chemically stable and nonreactive compounds that arise nonenzymatically from the spontaneous decomposition of lipid hydroperoxides. These hydroperoxides may decompose along other pathways, however, yielding highly reactive short chain alkenals such as 4-oxo-2-nonenal and 4-hydroxy-2-nonenal (HNE) (9 -17). HNE concentrations in human ventricular fluid are 8 -15 M and elevated in AD (3,18,19). HNE has a well known propensity to react with the side chains of various amino acid residues, and HNE-protein adducts have been used as biomarkers of oxidative stress (15).In light of these observations, it is noteworthy that lipid oxidation products such as HNE modify A and increase A misfolding (20 -25). Moreover, the immunoreactivity of antibodies to HNE-modified His residues localizes to amyloid plaques (26,27). This suggests that not only does A promote lipid oxidation but that there may also be a mechanistic link between the lipid oxidation products formed during oxidative stress and A misfolding (21). Conversely, several lines of evidence suggest that A contribute to oxidative stress. For example, the overexpression of A in transgenic mice, in Caenorhabditis elegans, and in cell culture results in an increase in...
The mechanism for the ethanol-induced aggregation/fusion of uniform-sized small liposomes comprised of dipalmitoyl (DPPC) or egg yolk (eggPC) phosphatidylcholines was studied by measuring the average size using a photon correlation spectroscopy, by observing directly the states in the liposomal solutions using freeze-fracture electron microscopy and by attempting resonance energy transfer using flurophore-labeled phospholipids. Abrupt increases in the apparent size of DPPC liposomes were observed in the presence of above 44 mg/ml ethanol, where microscopically plateau membranes form interdigitated structure, in which the acyl chains fully interpenetrate the hydrocarbon chains of the apposing monolayer. On the contrary, in the eggPC liposome, where the membranes cannot form interdigitated structures even in the presence of high concentration of ethanol, such intense aggregation and fusion were not observed, suggesting their intimate relation to the interdigitated structure formation. The formation of interdigitated structures in the adhering region leads to an increase in the interfacial area and an exposure of hydrophobic acyl chain terminal on the surface area, and enhances hydrophobic interactions between two interdigitated bilayers. Thus, the resultant interdigitated structure makes the aggregated state stable and partially initiates the bilayer mixing between the two apposed membranes, leading to fusion.
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