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Biomedical subjects

W E Müller

Publications and source records attributed to W E Müller.

At least 19 recordsLinked to original sources
PubMed2006

Apolipoprotein E epsilon 4 is associated with an increased vulnerability to cell death in Alzheimer's disease.

The presumption to suffer from Alzheimer's disease (AD) accelerates with aging. One important risk factor seems to be the isoform epsilon 4 of the apolipoprotein E gene (Apo epsilon 4), which increases the risk to develop AD at an earlier age. Furthermore, convincing evidence is provided that apoptotic cell death mechanisms play an important role in neuronal cell death in AD. In the present study, we investigated whether abnormalities in apoptosis and caspase-3 activity can be found at the level of lymphocytes and a T cell subtype, CD4 T cells, from AD patients compared to aged sex- and ApoE genotype-matched non-demented controls. Under different experimental conditions (at baseline or after in vitro incubation in the presence of proapoptotic stimuli) increased levels of apoptosis and enhanced caspase-3 activity were detected in lymphocytes from AD patients. This difference was most pronounced in the CD4(+) T cell subtype. Notably, we found a significant increase of apoptotic cells and caspase-3 activity in lymphocytes from AD patients bearing one or two alleles of the ApoE4 compared to non-E4 carriers. Again, these effects were strongest in CD4(+) T cells. Circulating amyloid-beta (A beta) levels did not differ between AD patients bearing ApoE4 and non-ApoE4 and age-matched controls. Therefore, it is likely that circulating A beta is not responsible for the observed effects, which might rather reflect an ongoing systemic response in AD, e.g. an increase in CD95 expression.

Aged↗
PubMed2006

The complexity of the dopaminergic synapses and their modulation by antipsychotics.

Since the mid of the 1960s, striking similarities between the psychosis seen in subjects taking high doses of amphetamines and the symptoms of patients with paranoid schizophrenia have been noted and placed in the context of increased catecholaminergic neurotransmission as a fundamental cause underlying major symptoms of the disease. Subsequent studies emphasized the contribution of central dopaminergic mechanisms for at least several psychotic symptoms of schizophrenia. The most compelling pharmacological data to support the developing "dopamine hypothesis of schizophrenia" originated from the clear relationship between antipsychotic drug efficacy and affinity for D2-like dopamine receptors strongly indicating D2-antagonism as major if not exclusive mechanism of antipsychotic drug action. Accordingly, in this review we focus on the neuropharmacology of the dopaminergic system in our brain with special emphasis on the dopaminergic synapse.

Animals↗
PubMed2006

Apoptosis of CD4+ T and natural killer cells in Alzheimer's disease.

BACKGROUND: Immunotherapy appears to be a potent treatment against Alzheimer's disease (AD), but the mechanisms underlying neural-immune interaction are still not known. METHODS: Here, we determined cell death and distribution of lymphocyte subsets of peripheral blood mononuclear cells (PBMC) in AD and aging, e.g. T (CD4+ CD3+, CD8+ CD3+), B (CD19+) and NK (CD16++CD56+) cells. RESULTS: Increased apoptosis was found in CD4+ T and NK cells in AD, while in aging all subsets were affected. The expression of anti-apoptotic Bcl2 correlated with observed cell death in T-helper and B cells irrespective of dementia. The levels of Bcl2 in T-cells were significantly increased in mild AD. Apoptosis and Bcl2 levels were also elevated in the APP (751SL)xPS1 (M146L) transgenic mouse model. CONCLUSION: The mechanisms triggering apoptosis and activation of lymphocytes in AD appear therefore to be different than those in immunosenescence and possibly bear an important biomarker to monitor immunotherapy in AD.

Adult↗
PubMed2006

Plant foods and brain aging: a critical appraisal.

In the 21st century, human aging will be one of the biggest challenges for most societies throughout the world. The decline in human fitness is a typical hallmark of the aging process. Aside from the cardiovascular system, the brain most often suffers significantly from the life-long impact of stressors, such as reactive oxygen and nitrogen species. Oxytosis, i.e. oxidative stress-induced cell death, has been identified to play a major role in the development and onset of chronic diseases. Foods, especially of plant origin, are rich in antioxidants and numerous in vivo data suggest that a diet rich in fruits and vegetables supports the maintenance of animal and human health. These beneficial effects also extend to the central nervous system, which, due to the presence of the blood-brain barrier, tightly controls the influx of metabolites and nutrients. In earlier studies the impact of antioxidant vitamins, such as alpha-tocopherol and ascorbic acid, on brain health has been of interest. Recently, the focus moved to assessing the potential of unsaturated fatty acids and secondary plant metabolites, particularly of polyphenols, to act as neuroprotectants. Considerable experimental evidence suggests that polyphenols and other plant-derived bioactivities affect animal and human brain function not only by directly lowering oxidative stress load but also by modulating various signal transduction pathways.

Aged↗
PubMed2005

Statins: drugs for Alzheimer's disease?

Evidences from cell culture experiments and animal studies suggest a strong link between cholesterol and Alzheimer's disease (AD). This relationship is supported by retrospective epidemiological studies demonstrating that statin treatment reduced the prevalence of AD in patients suffering from hypercholesterolaemia. The alternative processing of the amyloid-precursor protein (APP) in the brain of AD patients leads to the production of the neurotoxic amyloid-beta protein (Abeta), a causative factor for AD pathology. In vitro, this mechanism is modulated by alterations in cellular cholesterol levels. Moreover, lowering cholesterol in animal experiments reduced the production of Abeta in most but not all studies. These findings led to prospective clinical trials of cholesterol-lowering statins in AD patients, even if many studies do not support elevated cholesterol levels in serum and brain as a risk factor for Alzheimer's disease. Most of these studies were negative. Thus, up to date there is insufficient evidence to suggest the use of statins for treatment in patients with AD.

Alzheimer Disease↗
PubMed2005

[Selective serotonin and noradrenaline reuptake inhibitors: a step forward in the treatment of depression?].

With the tricyclics, selective serotonin reuptake inhibitors (SSRIs) and other substances, we now have available a range of medications for the treatment of depression and other psychological disorders (e.g. anxiety, panic). Nevertheless, only some of the patients experience a remission of their depressive symptoms. The occurrence of side effects and the only modest level of effectiveness result in inadequate compliance on the part of the patient. With venlafaxine and duloxetine two representatives of the selective serotonin and noradrenaline reuptake inhibitor (SSNRI) class of antidepressants are now available. SSNRIs have a dual effect coupled with high selectivity. The present article the extent to which this particular action mechanism results in an improved clinical efficacy and tolerability profile of the SSNRIs, in particular in comparison with SSRIs.

Antidepressive Agents↗
PubMed2005

Membrane disordering effects of beta-amyloid peptides.

The interaction of Abeta with synaptosomal plasma membranes decreases membrane fluidity. Using model membrane/liposome systems the interaction of Abeta with specific lipids (e.g. phospholipids, gangliosides, cholesterol) has been defined. The formation of the beta-sheet structure of Abeta when undergoing peptide aggregation is important for Abeta's membrane perturbing properties. This effect can be correlated with the peptide length of Abeta, the longer Abeta1-42 having the greatest effect on membrane fluidity and on neurotoxicity.

Alzheimer Disease↗
PubMed2005

Inhibition of P-glycoprotein function by several antidepressants may not contribute to clinical efficacy.

INTRODUCTION: In many depressive patients the negative feedback mechanism of the HPA (hypothalamic-pituitary-adrenocortical) axis is impaired. It has been suggested that antidepressants inhibit membrane glucocorticoid transporters like P-Glycoprotein (Pgp) and hence enhance the intracellular glucocorticoid concentration, leading to an increased glucocorticoid-receptor mediated gene transcription and therefore to normalization of the function of the HPA axis. The aim of this study is to investigate inhibition of Pgp by several different antidepressants. METHODS: We characterized the inhibitory potencies of the antidepressants in two in vitro assays by using calcein-AM as Pgp substrate. The two different cell-systems expressing Pgp were: 1. PBCEC (porcine brain capillary endothelial cells) as model for the blood-brain-barrier, and 2. A human lymphocytic leukaemia cell line CEM and the multi-drug-resistant (MDR) cell line VLB-100, expressing Pgp as model for the human protein. RESULTS: All of the antidepressants tested inhibit the transport of calcein-AM by Pgp in the micromolecular range. DISCUSSION: Because this inhibition is only seen at concentrations above therapeutically relevant plasma levels, their effect my not play a role for the mechanism of action of the antidepressants tested.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Enhanced ROS-generation in lymphocytes from Alzheimer's patients.

INTRODUCTION: Reactive oxygen species (ROS) have been implicated in neurodegeneration and seem to be involved in the physiology and pathophysiology of several diseases, including normal aging and Alzheimer's disease (AD). Enhanced ROS production in aging or AD is not restricted to the brain, but can also been seen in several peripheral tissues. The objective of the present study was to evaluate whether the mechanisms involved in the generation of oxidative stress in normal senescence and Alzheimer's disease are identical or not. METHODS: We analysed intracellular basal levels of ROS in lymphocytes from AD patients and healthy young and aged not-demented subjects as well as ROS levels following stimulation with d-ribose and staurosporine in all three groups. ROS levels were measured by flow cytometry using the intracellular fluorescence dye dihydrorhodamine123 (DHR123). RESULTS: Our study shows that AD lymphocytes have increased basal levels of ROS, low susceptibility to ROS stimulation by 2-deoxy- D-ribose (dRib) and an increased response to staurosporine when compared with age-matched controls. DISCUSSION: The data suggest that the defect(s) responsible for enhanced ROS production in AD may involve different or additional biological pathways than those involved in enhanced ROS generation during aging.

Adult↗
PubMed2005

Flavonoids and the aging brain.

Like in all other organs, the functional capacity of the human brain deteriorates over time. Pathological events such as oxidative stress, due to the elevated release of free radicals and reactive oxygen or nitrogen species, the subsequently enhanced oxidative modification of lipids, protein, and nucleic acids, and the modulation of apoptotic signaling pathways contribute to loss of brain function. The identification of neuroprotective food components is one strategy to facilitate healthy brain aging. Flavonoids were shown to activate key enzymes in mitochondrial respiration and to protect neuronal cells by acting as antioxidants, thus breaking the vicious cycle of oxidative stress and tissue damage. Furthermore, recent data indicate a favorable effect of flavonoids on neuro-inflammatory events. Whereas most of these effects have been shown in vitro, limited data in vivo are available, suggesting a rather low penetration of flavonoids into the brain. Nevertheless, several reports support the concept that flavonoid intake inhibits certain biochemical processes of brain aging, and might thus prevent to some extent the decline of cognitive functions with aging as well as the development or the course of neurodegenerative diseases. However, more data are needed to assess the true impact of flavonoids on brain aging.

Aging↗
PubMed2005

Antioxidant properties of Mediterranean food plant extracts: geographical differences.

Locally grown, wild food plants seasonally contribute a considerable portion of the daily diet in certain Mediterranean areas and it has been suggested that the beneficial effects of the Mediterranean diet on human health partly originate from the antioxidant effect of flavonoid-rich food plants. The nutrient content of most wild plants is higher than that of cultivated ones and may vary depending on the prevailing environmental conditions. Accordingly, three local Mediterranean plant foods (i.e. Cichorium intybus, Sonchus oleraceus, Papaver rhoeas) were collected in Greece (Crete), southern Italy, and southern Spain in order to assess possible differences in their in vitro antioxidant potential. The biological assays revealed diverse intra-plant specific antioxidant effects for the tested extracts ranging from no activity to almost complete protection. Furthermore, substantial differences in the polyphenol content were found for the nutritionally used part of the same plant originating from different locations. However, no clear correlations between the polyphenol content and the extracts' antioxidant activities were found. Taken together, the data suggest that certain local Mediterranean plant foods possess promising antioxidant activity and that the observed biological effects are possibly influenced by the geographically-dependent environmental conditions prevailing during plant growth.

Animals↗
PubMed2004

Murine synaptosomal lipid raft protein and lipid composition are altered by expression of human apoE 3 and 4 and by increasing age.

Apolipoprotein E (apoE) 4 and aging are risk factors for Alzheimer's disease (AD). Mice expressing human apoE4 and aged wild-type mice show a similarity in the transbilayer distribution of cholesterol in synaptic plasma membranes (SPMs) but differ markedly compared with apoE3 mice and young mice. The largest changes in cholesterol distribution were observed in the SPM exofacial leaflet where there was a doubling of cholesterol. Lipid rafts are thought to be associated with the exofacial leaflet, and we proposed that lipid raft protein and lipid composition would be associated with apoE genotype and age. Lipid rafts were isolated from synaptosomes of different age groups (2, 12, 24 months) of mice expressing human apoE3 and apoE4. Lipid raft markers, alkaline phosphatase (ALP), flotillin-1, cholesterol and sphingomyelin (SM) were examined. Lipid rafts of young apoE4 mice were more similar to older mice as compared with young apoE3 mice in reductions in alkaline phosphatase activity and flotillin-1 abundance. Lipid raft cholesterol and sphingomyelin levels were not significantly different between the young apoE3 and apoE4 mice but cholesterol levels of lipid rafts did increase with age in both genotypes. Results of the present study demonstrate that the two risk factors for Alzheimer's disease, apoE4 genotype and increasing age have similar effects on brain lipid raft protein markers and these findings support the notion that the transbilayer distribution of cholesterol is associated with lipid raft function.

Aging↗
PubMed2004

Impact of gender on upregulation of antioxidant defence mechanisms in Alzheimer's disease brain.

Since oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD) and since the age-adjusted incidence of AD is higher in females than males, we examined a possible influence of gender on antioxidant metabolism in brains from male and female AD patients and age-matched controls. Activities of copper/zinc-dependent superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-disulfide reductase (GR) were elevated in AD samples compared to controls. Upon in vitro stimulation, levels of malondialdehyde formation were significantly lower in AD samples, probably due to the increased antioxidant capacity. Overall, our results indicate that antioxidant metabolism is functionally still intact but increased in AD implying that oxidative damage is caused rather by overproduction than by insufficient detoxification of ROS. Among AD patients, a gender-specific partial upregulation of antioxidant defence was present: activities of SOD and GPx were even further increased in female patients, and levels of 4-hydroxynonenal, a marker of oxidative damage, were higher than in male patients. Importantly, our results are in line with epidemiological studies indicating a higher risk for AD in females. Thus, gender differences in oxidative stress parameters might be related to the higher prevalence of AD in females.

Aged↗
PubMed2004

Effect of chronic antidepressant treatment on beta-receptor coupled signal transduction cascade. Which effect matters most?

BACKGROUND: Beta-receptor down-regulation has been described as a common biochemical effect of chronic treatment with many but not all antidepressant drugs. Beta-receptor activation leads to elevated intracellular levels of cAMP followed by the activation of several protein kinases which in turn activate various transcription factors. One of those, CREP has received increasing interest as an relevant component within the antidepressant drug modulated signal cascade as it represents a down-stream signal not only of the beta-receptor but also of serotonin receptor activation. Chronic treatment with many antidpressant drugs has been shown to alter CREP levels in several brain regions. While beta-receptor down-regulation by chronic antidepressant treatment has been a consistent finding, alterations of CREP levels have been observed in both direction. Similarly divergent findings have been reported for BDNF a major gene targeted of CREB, where most but not all findings suggest up-regulation at least at the message level following chronic antidepressant treatment. METHODS: Because of these rather divergent data, we investigated the possible effects of chronic treatment (9 or 19 days) with three different antidepressant drugs (reboxetine, citalopram, imipramine) on the individual parameters of the beta-receptor coupled signal transduction cascade. All animals were also tested for possible antidepressant effects using the forced swimming test. RESULTS: While beta-receptor density was down-regulated by reboxetine and imipramine but not citalopram, CREB protein was only mildly elevated after 9 days, and not changed or slightly reduced after 19 days. BDNF protein levels were not or only slightly enhanced, but only for the 9 days treatment. Citalopram was most active. Under the conditions chosen, all three drugs were active in the forced swimming test. CONCLUSION: Taken together, the findings reported make it difficult to identify one single component of the beta-receptor coupled signal transduction cascade as common final target of chronic antidepressant treatment.

Adrenergic Agents↗
PubMed2004

Editorial.

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Binding Sites↗
PubMed2004

Neuropharmacology of the anxiolytic drug opipramol, a sigma site ligand.

Although opipramol is structurally related to imipramine, it does not represent a tricyclic antidepressant drug as it does not inhibit the neuronal uptake of norepinephrine and/or serotonin. Unlike imipramine it is a rather potent sigma ligand with modest subclass selectivity which is similar in vitro as well as ex vivo. Opipramol is active in several behavioural paradigms indicative of anxiolytic properties at doses (1-10 mg/kg), which are also needed to occupy sigma binding sites. Somewhat higher doses (10-20 mg/kg) are needed for "antidepressant like" effects. The data allow the conclusion that interaction with sigma sites is involved in the anxiolytic and antidepressant effects of opipramol albeit a contribution of its weaker D (2)-antagonistic and 5-HT2-antagonistic properties cannot be totally be excluded.

Analysis of Variance↗
PubMed2004

Modulation of P-glycoprotein function by St John's wort extract and its major constituents.

INTRODUCTION: Recent data suggest some relevant drug interactions caused by St John's wort extract, which can be explained by interactions with the Cytochrome P450 system or P-Glycoprotein (Pgp). Interaction with Pgp, including activation, inhibition and induction, can lead to altered plasma or brain levels of Pgp substrates. The aim of the present study was to investigate the possible interactions of St John's wort extract and most relevant constituents with the transport activity of Pgp. METHODS: We characterized the modulatory potencies in two in vitro assays using calcein-AM, first in VLB cells (a human lymphocytic leukemia cell line expressing Pgp) and second in PBCEC cells (porcine brain capillary endothelial cells). RESULTS: The extract, as well as some of the tested constituents modulate the transport by Pgp in the micromolecular range. Quercetin and hyperforin seem to be most potent. CONCLUSIONS: These findings suggest the possibility of drug interactions at the level of the gastro-intestinal absorption of drugs. Plasma levels of the constituents of St John's wort are very likely too low to interfere with Pgp at the blood-brain-barrier with the possible exception of quercetin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗