Increasing Age Alters Transbilayer Fluidity and Cholesterol Asymmetry in Synaptic Plasma Membranes of Mice

Igbavboa, Urule; Avdulov, N. A.; Schroeder, Friedhelm; Wood, W. G.

doi:10.1046/j.1471-4159.1996.66041717.x

Cited by 154 publications

(117 citation statements)

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“…5b). In fact, the concentration of cholesterol in the cytofacial leaflet of brain synaptic plasma membrane is lower in aged people (60), and A␤ cannot insert into the membrane containing less cholesterol (61). Once A␤ exits the membrane and enters into the extracellular solution, the segment of residues 29-40 has a high tendency to form short ␤-sheets (Figs.…”

Section: Discussionmentioning

confidence: 99%

Conformational transition of amyloid β-peptide

Shen

Luo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

243

259

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The amyloid ␤-peptides (A␤s), containing 39 -43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of A␤40, 12 independent long-time molecular dynamics (MD) simulations for a total of 850 ns were performed on both the wide-type peptide and its mutant in both aqueous solution and a biomembrane environment. In aqueous solution, an ␣-helix to ␤-sheet conformational transition for A␤40 was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with ␤-sheet components were observed as intermediates in the unfolding pathway of A␤40. Four glycines (G25, G29, G33, and G37) are important for A␤40 to form ␤-sheet in aqueous solution; mutations of these glycines to alanines almost abolished the ␤-sheet formation and increased the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of A␤40 is a helix; however, the peptide tends to exit the membrane environment and lie down on the surface of the bilayer. The dynamic feature revealed by our MD simulations rationalized several experimental observations for A␤40 aggregation and amyloid fibril formation. The results of MD simulations are beneficial to understanding the mechanism of amyloid formation and designing the compounds for inhibiting the aggregation of A␤ and amyloid fibril formation. molecular dynamics simulation A lzheimer's disease (AD), a neurodegenerative disorder, is pathologically characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles in the brain (1). The major components of the plaques are amyloid ␤-peptides (A␤s) consisting of 39-43 residues that are proteolytically derived from the widely distributed transmembrane amyloid precursor glycoprotein (APP) (2-4). The amyloid hypothesis suggests that misfolding of A␤ leads to its dysfunctions and fibrillization; the latter is associated with a cascade of neuropathogenetic events to produce the cognitive and behavioral decline hallmarks of AD (4-6). Recently, however, compelling evidence has emerged that not the fibrillar aggregates but the dominant ␤-sheet structure of oligomers and fibril intermediates (protofibrils) are neurotoxic and might be the determinant pathogenic factor in AD (7-9). For example, Walsh et al. (8) demonstrated that cerebral microinjection of cell medium containing abundant A␤ monomers and oligomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation in rats in vivo. The conflict between the amyloid hypothesis and these new emerging experimental observations has stimulated more and more researchers to study the earliest phases of A␤ assembly and to explore the intrinsic properties of A␤s and the conformational dynamic behaviors of the A␤ monomer (9-15).In addition, it has been established experimentally that the major secondary structure adopted by A␤ depends on the environment. The A␤ monomer favors an ␣-helix structure in a me...

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Section: Discussionmentioning

confidence: 99%

Conformational transition of amyloid β-peptide

Shen

Luo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

243

259

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“…in (12,144,145). DHE revealed that the cytofacial leaflet of plasma membranes from L-cell fibroblasts (12,24,146,147), erythrocytes (144), and brain synaptosomes (145,(148)(149)(150)(151). While other methods (filipin staining, exchange, cholesterol oxidase accessibility, neutron diffraction, etc) have also been used to measure transbilayer cholesterol distribution, many have significant limitations including accessibility of membrane cholesterol (filipin, cholesterol oxidase), production of a potential perturbant (cholesterol oxidase produces cholesterone), and poor dynamic resolution (neutron diffraction) (rev.…”

Section: Dhe Architecture In Purified Biological Membranesmentioning

confidence: 99%

“…While measurements of transbilayer sterol distribution by different methods may therefore not necessarily agree, multiple methods (DHE, NBD-cholesterol quenching, and exchange assays) indicate that the cytofacial leaflet of erythrocytes has more cholesterol than the exofacial leaflet (144,152). Likewise, several methods (DHE, cholesterol oxidase) indicate that the synaptosomal plasma membrane has more cholesterol in the cytofacial leaflet than the exofacial leaflet (12,145,(148)(149)(150). The transbilayer distribution of sterol is a major determinant of the transbilayer fluidity gradient present in these membranes, the cytofacial cholesterol-rich leaflet is more rigid (less fluid) than the relatively cholesterol-poor exofacial leaflet (rev.…”

Section: Dhe Architecture In Purified Biological Membranesmentioning

confidence: 99%

“…The transbilayer distribution of sterol is a major determinant of the transbilayer fluidity gradient present in these membranes, the cytofacial cholesterol-rich leaflet is more rigid (less fluid) than the relatively cholesterol-poor exofacial leaflet (rev. in (146,147,149,(153)(154)(155)(156)(157)(158)(159). The transbilayer migration rate of DHE in model membranes and plasma membranes is relatively fast, t 1/2 of sec-min depending on the membrane examined (rev.…”

Section: Dhe Architecture In Purified Biological Membranesmentioning

confidence: 99%

“…The finding of rapid transbilayer sterol movement suggested that the asymmetric transbilayer distribution in the plasma membrane was not due to restricted movement of cholesterol from one leaflet to the other, but was instead a property of the lipid bilayer itself. DHE transbilayer distribution has broad applicability in studies of the action of anesthetics, cholesterol lowering drugs (statins), alcohol (chronic and acute), lupus erythematosus, aging, apoE, and sterol carrier proteins all of which can alter plasma membrane or synaptosomal plasma membrane transbilayer sterol distribution and/or transbilayer fluidity (26,135,136,145,149,150,154,(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171)(172).Second, the DHE lateral distribution in both model and biological membranes was not uniform, but instead reflected sterol-rich and poor domains (rev. in (54,55).…”

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Fluorescence Techniques Using Dehydroergosterol to Study Cholesterol Trafficking

McIntosh

Atshaves

Huang

et al. 2008

Lipids

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Cholesterol itself has very few structural/chemical features suitable for real-time imaging in living cells. Thus, the advent of dehydroergosterol [ergosta-5,7,9(11),22-tetraen-3β-ol, DHE] the fluorescent sterol most structurally and functionally similar to cholesterol to date, has proven to be a major asset for real-time probing/elucidating the sterol environment and intracellular sterol trafficking in living organisms. DHE is a naturally-occurring, fluorescent sterol analog that faithfully mimics many of the properties of cholesterol. Because these properties are very sensitive to sterol structure and degradation, such studies require the use of extremely pure (>98%) quantities of fluorescent sterol. DHE is readily bound by cholesterol-binding proteins, is incorporated into lipoproteins (from the diet of animals or by exchange in vitro), and for real-time imaging studies is easily incorporated into cultured cells where it co-distributes with endogenous sterol. Incorporation from an ethanolic stock solution to cell culture media is effective, but this process forms an aqueous dispersion of dehydroergosterol crystals which can result in endocytic cellular uptake and distribution into lysosomes which is problematic in imaging DHE at the plasma membrane of living cells. In contrast, monomeric DHE can be incorporated from unilamellar vesicles by exchange/fusion with the plasma membrane or from DHE-methyl-β-cyclodextrin (DHE-MβCD) complexes by exchange with the plasma membrane. Both of the latter techniques can deliver large quantities of monomeric dehydroergosterol with significant distribution into the plasma membrane. The properties and behavior of DHE in protein-binding, lipoproteins, model membranes, biological membranes, lipid rafts/caveolae, and real-time imaging in living cells indicate that this naturally-occurring fluorescent sterol is a useful mimic for probing the properties of cholesterol in these systems. Keywordsdehydroergosterol; cholesterol; ergosterol; fluorescent sterols; microscopy Historical PerspectiveIn order to resolve the dynamics and factors governing cholesterol trafficking within cells, it is important to recognize that the cholesterol molecule has very few polar constituents (Fig. 1A). Consequently, cholesterol is poorly soluble in aqueous environments such as cytosol as evidenced by critical micellar concentrations of cholesterol and other sterols being very low, *To whom correspondence should be addressed: Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 862-1433, FAX: (979) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript near 20-30 nM (1-5). The physiological impact of cholesterol's low aqueous solubility is that spontaneous cholesterol desorption from the cytofacial leaflet of the plasma membrane or lysosomal membrane into the cytosol for transfer to intracellular sites for esterification, oxidation, or secretion is extremely slow (t 1/2 3 hours-days) (6-9). Therefore, it is important to resolve factors...

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A unifying hypothesis of Alzheimer's disease. III. Risk factors

Heininger

2000

Hum. Psychopharmacol. Clin. Exp.

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Normal ageing and Alzheimer's disease (AD) have many features in common and, in many respects, both conditions only differ by quantitative criteria. A variety of genetic, medical and environmental factors modulate the ageing-related processes leading the brain into the devastation of AD. In accordance with the concept that AD is a metabolic disease, these risk factors deteriorate the homeostasis of the Ca(2+)-energy-redox triangle and disrupt the cerebral reserve capacity under metabolic stress. The major genetic risk factors (APP and presenilin mutations, Down's syndrome, apolipoprotein E4) are associated with a compromise of the homeostatic triangle. The pathophysiological processes leading to this vulnerability remain elusive at present, while mitochondrial mutations can be plausibly integrated into the metabolic scenario. The metabolic leitmotif is particularly evident with medical risk factors which are associated with an impaired cerebral perfusion, such as cerebrovascular diseases including stroke, cardiovascular diseases, hypo- and hypertension. Traumatic brain injury represents another example due to the persistent metabolic stress following the acute event. Thyroid diseases have detrimental sequela for cerebral metabolism as well. Furthermore, major depression and presumably chronic stress endanger susceptible brain areas mediated by a host of hormonal imbalances, particularly the HPA-axis dysregulation. Sociocultural and lifestyle factors like education, physical activity, diet and smoking may also modulate the individual risk affecting both reserve capacity and vulnerability. The pathophysiological relevance of trace metals, including aluminum and iron, is highly controversial; at any rate, they may adversely affect cellular defences, antioxidant competence in particular. The relative contribution of these factors, however, is as individual as the pattern of the factors. In familial AD, the genetic factors clearly drive the sequence of events. A strong interaction of fat metabolism and apoE polymorphism is suggested by intercultural epidemiological findings. In cultures, less plagued by the 'blessings' of the 'cafeteria diet-sedentary' Western lifestyle, apoE4 appears to be not a risk factor for AD. This intriguing evidence suggests that, analogous to cardiovascular diseases, apoE4 requires a hyperlipidaemic lifestyle to manifest as AD risk factor. Overall, the etiology of AD is a key paradigm for a gene-environment interaction. Copyright 2000 John Wiley & Sons, Ltd.

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Increasing Age Alters Transbilayer Fluidity and Cholesterol Asymmetry in Synaptic Plasma Membranes of Mice

Cited by 154 publications

References 18 publications

Conformational transition of amyloid β-peptide

Conformational transition of amyloid β-peptide

Fluorescence Techniques Using Dehydroergosterol to Study Cholesterol Trafficking

A unifying hypothesis of Alzheimer's disease. III. Risk factors

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