Biomedical subjects

W Gibson Wood

Publications and source records attributed to W Gibson Wood.

16 recordsLinked to original sources

PubMed2006

Bcl-2 upregulation and neuroprotection in guinea pig brain following chronic simvastatin treatment.

The present study determined if chronic simvastatin administration in vivo would provide neuroprotection in brain cells isolated from guinea pigs after challenge with the Bcl-2 inhibitor HA 14-1 or the NO donor sodium nitroprusside (SNP). Bcl-2 levels were significantly increased in brains of simvastatin-treated guinea pigs while levels of the pro-apoptotic protein Bax were significantly reduced. The ratio of Bax/Bcl-2, being a critical factor of the apoptotic state of cells, was significantly reduced in simvastatin-treated animals. Cholesterol levels in the brain remained unchanged in the simvastatin group. Brain cells isolated from simvastatin-treated guinea pigs were significantly less vulnerable to mitochondrial dysfunction and caspase-activation. These results provide new insight into potential mechanisms for the protective actions of statins within the CNS where programmed cell death has been implicated.

Animals↗

PubMed2006

Cholesterol distribution, not total levels, correlate with altered amyloid precursor protein processing in statin-treated mice.

There are now a number of studies that suggest that cholesterol might regulate the processing of the amyloid precursor protein to form the neurotoxic peptide Abeta. This research has opened the possibility that cholesterol-lowering drugs might be efficacious as anti-Abeta drugs for use in Alzheimer's disease. The use of HMG-CoA reductase inhibitors (commonly called statins) in vitro and in vivo has proven them to be Abeta-lowering agents, however, the mechanism of action of these drugs is not yet known. One possible mechanism is that they reduce Abeta levels indirectly by reducing cholesterol in the central nervous system (CNS). In this study, we administered three different statins (simvastatin, lovastatin, and atorvastatin) to nontransgenic mice. We found that all three compounds had similar effects on Abeta, reducing both Abeta40 and Abeta42. The statins decreased beta-cleaved C-terminal fragment (CTF) although having no effect on alpha-CTF levels. However, the drugs did not have a similar effect on cholesterol in the CNS. Only lovastatin significantly reduced total cholesterol in isolated plasma membranes. As cholesterol is not distributed evenly in the plasma membrane, we examined bilayer distribution of cholesterol and found that all three statins caused CNS cholesterol to translocate from the cytofacial leaflet to the exofacial leaflet. This data suggests that cholesterol distribution and not total cholesterol levels may be important to Abeta production in the CNS.

Amyloid beta-Peptides↗

PubMed2005

In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid.

The beta-amyloids (abetas) are the major components of the plaque observed in the brains of patients with Alzheimer's disease. The conundrum is that although they are produced in everyone during the posttranslational processing in the endoplasmic reticulum (ER) of the amyloid precursor protein (APP), deposits are only observed in the elderly. Our work suggests that normals have a carrier protein(s) keeping them in solution. Based on immunoblotting studies of cerebrospinal fluid (CSF) from normals, we find that the bulk of the abetas are bound to the ER chaperones, ERp57 and calreticulin, suggesting that these may be carrier proteins which prevent aggregation of the abetas and that the deposits are due to faulty ER posttranslational processing of APP with the failure to form this complex. If membrane protein synthesis is similarly affected, it could explain the neuronal dysfunction characteristic of Alzheimer's disease.

Aging↗

PubMed2005

Phospholipase A2 in astrocytes: responses to oxidative stress, inflammation, and G protein-coupled receptor agonists.

Astrocytes comprise the major cell type in the central nervous system (CNS) and they are essential for support of neuronal functions by providing nutrients and regulating cell-to-cell communication. Astrocytes also are immune-like cells that become reactive in response to neuronal injury. Phospholipases A2 (PLA2) are a family of ubiquitous enzymes that degrade membrane phospholipids and produce lipid mediators for regulating cellular functions. Three major classes of PLA2 are expressed in astrocytes: group IV calcium-dependent cytosolic PLA2 (cPLA2), group VI calcium-independent PLA2 (iPLA2), and group II secretory PLA2(sPLA2). Upregulation of PLA2 in reactive astrocytes has been shown to occur in a number of neurodegenerative diseases, including stroke and Alzheimer's disease. This review focuses on describing the effects of oxidative stress, inflammation, and activation of G protein-coupled receptors on PLA2 activation, arachidonic acid (AA) release, and production of prostanoids in astrocytes.

Animals↗

PubMed2005

Is hypercholesterolemia a risk factor for Alzheimer's disease?

There is considerable attention being given to the association of Alzheimer's disease and cholesterol homeostasis. To that end, some have suggested that elevated cholesterol levels are a risk factor for Alzheimer's disease. If elevated cholesterol is a risk factor for Alzheimer's disease, then it would be expected that patients with Alzheimer's disease would have elevated serum and brain cholesterol levels. Studies were reviewed that have examined cholesterol levels in Alzheimer's patients and control subjects, including prospective studies, and based on that review, the conclusion is reached that the majority of studies do not support elevated cholesterol levels in serum and brain as a risk factor for Alzheimer's disease. Alternative hypotheses are discussed, including cholesterol domains and subgroups of individuals with hypercholesteremia.

Alzheimer Disease↗

PubMed2004

Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex.

Statins have been reported to lower the risk of developing Alzheimer's disease; however, the mechanism of this potentially important neuroprotective action is not understood. Lowering cholesterol levels does not appear to be the primary mechanism. Statins have pleiotropic effects in addition to lowering cholesterol, and statins may act on several different pathways involving distinct gene expression patterns that would be difficult to determine by focusing on a few genes or their products in a single study. In addition, gene expression patterns may be specific to a particular statin. To understand the molecular targets of statins in brain, DNA microarrays were used to identify gene expression patterns in the cerebral cortex of mice chronically treated with lovastatin, pravastatin, and simvastatin. Furthermore, brain statin levels were determined using liquid chromatography/tandem mass spectrometry. These studies revealed 15 genes involved in cell growth and signaling and trafficking that were similarly changed by all three statins. Overall, simvastatin had the greatest influence on expression as demonstrated by its ability to modify the expression of 23 genes in addition to those changed by all three drugs. Of particular interest was the expression of genes associated with apoptotic pathways that were altered by simvastatin. Reverse transcription-polymerase chain reaction experiments confirmed the microarray findings. All three drugs were detected in the cerebral cortex, and acute experiments revealed that statins are relatively rapidly removed from the brain. These results provide new insight into possible mechanisms for the potential efficacy of statins in reducing the risk of Alzheimer's disease and lay the foundation for future studies.

Animals↗

PubMed2004

Accelerated Abeta aggregation in the presence of GM1-ganglioside-accumulated synaptosomes of aged apoE4-knock-in mouse brain.

Aging and apolipoprotein E4 (apoE4) expression are strong risk factors for the development of Alzheimer's disease (AD); however, their pathological roles remain to be clarified. In the process of AD development, the conversion of the nontoxic amyloid beta-protein (Abeta) monomer to its toxic aggregates is a fundamental process. We previously hypothesized that Abeta aggregation is accelerated through the generation of GM1 ganglioside (GM1)-bound Abeta which acts as a seed for Abeta fibril formation. Here we report that GM1 level in detergent-resistant membrane microdomains (DRMs) of synaptosomes increased with age and that this increase was significantly pronounced in the apoE4- than the apoE3-knock-in mouse brain. Furthermore, we show that Abeta aggregation is markedly accelerated in the presence of the synaptosomes of the aged apoE4-knock-in mouse brain. These observations suggest that aging and apoE4 expression cooperatively accelerate Abeta aggregation in the brain through an increase in the level of GM1 in neuronal membranes.

Aging↗

PubMed2003

Amyloid beta-protein interactions with membranes and cholesterol: causes or casualties of Alzheimer's disease.

Amyloid beta-protein (Abeta) is thought to be one of the primary factors causing neurodegeneration in Alzheimer's disease (AD). This protein is an amphipathic molecule that perturbs membranes, binds lipids and alters cell function. Several studies have reported that Abeta alters membrane fluidity but the direction of this effect has not been consistently observed and explanations for this lack of consistency are proposed. Cholesterol is a key component of membranes and cholesterol interacts with Abeta in a reciprocal manner. Abeta impacts on cholesterol homeostasis and modification of cholesterol levels alters Abeta expression. In addition, certain cholesterol lowering drugs (statins) appear to reduce the risk of AD in human subjects. However, the role of changes in the total amount of brain cholesterol in AD and the mechanisms of action of statins in lowering the risk of AD are unclear. Here we discuss data on membranes, cholesterol, Abeta and AD, and propose that modification of the transbilayer distribution of cholesterol in contrast to a change in the total amount of cholesterol provides a cooperative environment for Abeta synthesis and accumulation in membranes leading to cell dysfunction including disruption in cholesterol homeostasis.

Alzheimer Disease↗

PubMed2003

Cholesterol distribution in the Golgi complex of DITNC1 astrocytes is differentially altered by fresh and aged amyloid beta-peptide-(1-42).

The Golgi complex plays an important role in cholesterol trafficking in cells, and amyloid beta-peptides (Abetas) alter cholesterol trafficking. The hypothesis was tested that fresh and aged Abeta-(1-42) would differentially modify Golgi cholesterol content in DINTC1 astrocytes and that the effects of Abeta-(1-42) would be associated with the region of the Golgi complex. Two different methods were used to determine the effects of Abeta-(1-42) on Golgi complex cholesterol. Confocal microscopy showed that fresh Abeta-(1-42) significantly increased cholesterol and that aged Abeta-(1-42) significantly reduced cholesterol content in the Golgi complex. Isolation of the Golgi complex into two fractions using density gradient centrifugation showed effects of aged Abeta-(1-42) similar to those observed with confocal microscopy but revealed the novel finding that fresh Abeta-(1-42) had opposite effects on the two Golgi fractions suggesting a specificity of Abeta-(1-42) perturbation of the Golgi complex. Phosphatidylcholine-phospholipase D activity, cell membrane cholesterol, and apolipoprotein E levels were associated with effects of fresh Abeta-(1-42) on cholesterol distribution but not with effects of aged Abeta-(1-42), arguing against a common mechanism. Extracellular Abeta-(1-42) targets the Golgi complex and disrupts cell cholesterol homeostasis, and this action of Abeta-(1-42) could alter cell functions requiring optimal levels of cholesterol.

Amyloid beta-Peptides↗

PubMed2003

Lipid rafts of purified mouse brain synaptosomes prepared with or without detergent reveal different lipid and protein domains.

Lipid rafts have been proposed to be important in a variety of functions including lipid transport, signal transduction and cell growth. There is increasing evidence that lipid rafts may play a role in cell functions in brain. Lipid rafts are typically isolated using a detergent such as Triton X-100. There has been, however, data from non-brain tissue indicating that preparation of lipid rafts using a detergent may represent different raft domains as compared with non-detergent preparation. The purpose of the present study was to compare protein and lipid markers of lipid rafts using a highly purified mouse synaptosomal fraction and non-detergent and detergent methods. The lipid raft marker proteins, alkaline phosphatase and flotillin, and the lipid markers, cholesterol and sphingomyelin, were highly enriched in lipid rafts prepared with detergent as compared with the non-detergent fraction. Enrichment of Na(+),K(+)-ATPase was greater in the non-detergent lipid raft fraction as compared with lipid rafts prepared with detergent. Lipid rafts from the nerve terminal of neurons prepared with or without detergents may represent different membrane domains each with unique specialized functions.

Animals↗

PubMed2003

Cholesterol modulates amyloid beta-peptide's membrane interactions.

The causal relationship between amyloid beta-peptide (Abeta) deposition and Alzheimer's disease (AD)-specific neuropathological lesions such as neurodegeneration and cortical atrophy is still not known. Mounting evidence points to alterations in cholesterol homeostasis occurring in AD brain that are probably linked to cerebral Abeta pathology. Interestingly, cholesterol not only modulates Abeta synthesis, but also controls interactions between Abeta and neuronal membranes that are regarded as decisive in the initiation of a neurotoxic cascade. This review focuses on the impact of cholesterol on membrane disordering effects of Abeta. Cholesterol is known to be an essential modulator of physicochemical state and functional activity in physiological membranes, and thus plays an essential role in the regulation of synaptic function and cell plasticity. In vitro and in vivo modulation of membrane cholesterol levels affect different cholesterol pools within the plasma membrane bilayer that are differentially sensitive to Abeta's disrupting effects. Membrane acyl-chains in the hydrocarbon core are most susceptible to Abeta. In this membrane region, cholesterol attenuates the membrane disordering effects of Abeta. This cholesterol pool is modulated by methyl-beta-cyclodextrin (MbetaCD) treatment in vitro. On the other hand, statin treatment in vivo depletes a cholesterol pool in a membrane area, which is much less susceptible to Abeta's membrane-disrupting effects. Our findings clearly implicate an involvement of cholesterol in brain membrane alterations occurring during AD. Disease-related changes in membrane cholesterol metabolism may be subtle and restricted to defined membrane pools since total membrane cholesterol levels are mainly unchanged in AD brain. Thus, elucidation of the structure and function of different cholesterol pools is necessary in understanding the coherence between cholesterol and AD.

Alzheimer Disease↗

PubMed2002

Amphiphilic effects of local anesthetics on rotational mobility in neuronal and model membranes.

To provide a basis for studying the molecular mechanism of pharmacological action of local anesthetics, we carried out a study of the membrane actions of tetracaine, bupivacaine, lidocaine, prilocaine and procaine. Fluorescence polarization of 12-(9-anthroyloxy)stearic acid (12-AS) and 2-(9-anthroyloxy)stearic acid (2-AS) were used to examine the effects of local anesthetics on differential rotational mobility between polar region and hydrocarbon interior of synaptosomal plasma membrane vesicles (SPMV) isolated from bovine cerebral cortex, and liposomes of total lipids (SPMVTL) and phospholipids (SPMVPL) extracted from the SPMV. The two membrane components differed with respect to 2 and 12 anthroyloxy stearate (2-AS, 12-AS) probes, indicating that a difference in the membrane fluidity may be present. In a dose-dependent manner, tetracaine, bupivacaine, lidocaine, prilocaine and procaine decreased anisotropy of 12-AS in the hydrocarbon interior of the SPMV, SPMVTL and SPMVPL, but tetracaine, bupivacaine, lidocaine and prilocaine increased anisotropy of 2-AS in the membrane interface. These results indicate that local anesthetics have significant disordering effects on hydrocarbon interior of the SPMV, SPMVTL and SPMVPL, but have significant ordering effects on the membrane interface, and thus they could affect the transport of Na(+) and K(+) in nerve membranes, leading to anesthetic action.

Anesthetics, Local↗

PubMed2002

Cholesterol is increased in the exofacial leaflet of synaptic plasma membranes of human apolipoprotein E4 knock-in mice.

Inheritance of the apolipoprotein (apoE) epsilon4 allele is a risk factor for developing Alzheimer's disease (AD). The purpose of the present study was to determine effects of apoE-isoforms on the transbilayer distribution of cholesterol in synaptic plasma membranes (SPM) using mice expressing human apoE3 and apoE4. Total SPM cholesterol levels did not differ among the wild-type and apoE3 and apoE4 knock-in mice. However, a striking difference was observed in the transbilayer distribution of SPM cholesterol. ApoE4 knock-in mice showed an approximately 2-fold increase in exofacial leaflet cholesterol compared with apoE3 knock-in mice and wild-type mice. The results of this study suggest that pathogenic effects of apoE4 on AD development could be closely linked to alteration of cholesterol distribution in SPM.

Alzheimer Disease↗

PubMed2002

A new role for apolipoprotein E: modulating transport of polyunsaturated phospholipid molecular species in synaptic plasma membranes.

Phospholipids and their acyl group composition are important in providing the proper membrane environment for membrane protein structure and function. In particular, the highly unsaturated phospholipids in synaptic plasma membranes in the CNS are known to play an important role in modulating receptor function and neurotransmitter release processes. Apolipoprotein E (apoE) is a major apolipoprotein in the CNS, mediating the transport of cholesterol, phospholipids and their fatty acids, particularly in reparative mechanisms during neuronal injury. This study was performed to determine whether deficiency in the apoE gene contributes to an alteration of the phospholipids in synaptic plasma membranes. Phospholipid molecular species were identified and quantitated by HPLC/electrospray ionization-mass spectrometry. Analysis of the different phospholipid classes in membranes of apoE-deficient and C57BL/6 J mice indicated no obvious differences in the distribution of different phospholipid classes but substantial differences in composition of phospholipid molecular species. Of special interest was the prevalence of phospholipids (phosphatidylcholine, diacyl-phosphatidylethanolamine, and phosphatidylserine) with 22:6n-3 in both the sn-1 and sn-2 positions of SPM and these phospholipid species were significantly higher in apoE-deficient mice as compared to control mice. Since polyunsaturated fatty acids in neurons are mainly supplied by astrocytes, these results revealed a new role for apoE in regulating polyunsaturated phospholipid molecular species in neuronal membranes.

Alzheimer Disease↗

PubMed2001

Ethanol and lipid metabolic signaling.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Shivendra D. Shukla and Grace Y. Sun. The presentations were (1) Metabolic turnover of ethanol into cellular lipids and platelet activating factor, by Shivendra D. Shukla; (2) Ethanol action on the phospholipase A2 signaling pathways in astrocytes, by Grace Y. Sun; (3) Mechanisms of ethanol-induced perturbation of lipoprotein cholesterol transport, by W. Gibson Wood; (4) Transfer of an abnormal ethanol-induced phospholipid, phosphatidylethanol, between lipoproteins, by Markku J. Savolainen; (5) Phospholipase-d-mediated formation of phosphatidylethanol, by Christer Alling; and (6) Changes in phosphoinositide signaling after chronic ethanol treatment, by Jan B. Hoek.

Animals↗

PubMedDate not supplied

Brain membrane cholesterol domains, aging and amyloid beta-peptides.

Lipids are essential for the structural and functional integrity of membranes. Membrane lipids are not randomly distributed but are localized in different domains. These domains consist of the exofacial and cytofacial leaflets, cholesterol pools, annular lipids, and lipid rafts. Membrane lipid domains have been proposed to be involved in a variety of different functions including e.g. signal transduction, lipid transport and metabolism, and cell growth. Membrane lipid domains have been identified in brain and can be modified by different experimental conditions, aging and certain neurodegenerative diseases. Recent data reveal the very interesting possibility that membrane lipid domains may be a target of Alzheimer's disease. There is a growing body of evidence showing an association between cholesterol and Alzheimer's disease, and cholesterol is a major component of membrane lipid domains. Here we discuss recent data on brain membrane lipid domains emphasizing the structural and functional role of cholesterol. In addition, lipid domains and aging, and the potential interaction of lipid domains and amyloid beta-peptides (Abeta) that are a major component of senile plaques in brains of Alzheimer's patients are considered. We propose that age changes in the asymmetric distribution of cholesterol in contrast to total or bulk cholesterol in neuronal plasma membranes provides a cooperative environment for accumulation of Abeta in plasma membranes and the accumulation of Abeta is due in part to a direct physico-chemical interaction with cholesterol in the membrane exofacial or outer leaflet.

Aged↗