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Search Results: 1 - 10 of 5520 matches for " Markus Glatzel "
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Sympathetic Prions
Markus Glatzel
The Scientific World Journal , 2001, DOI: 10.1100/tsw.2001.258
N-Glycans and Glycosylphosphatidylinositol-Anchor Act on Polarized Sorting of Mouse PrPC in Madin-Darby Canine Kidney Cells
Berta Puig, Hermann C. Altmeppen, Dana Thurm, Markus Geissen, Catharina Conrad, Thomas Braulke, Markus Glatzel
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024624
Abstract: The cellular prion protein (PrPC) plays a fundamental role in prion disease. PrPC is a glycosylphosphatidylinositol (GPI)-anchored protein with two variably occupied N-glycosylation sites. In general, GPI-anchor and N-glycosylation direct proteins to apical membranes in polarized cells whereas the majority of mouse PrPC is found in basolateral membranes in polarized Madin-Darby canine kidney (MDCK) cells. In this study we have mutated the first, the second, and both N-glycosylation sites of PrPC and also replaced the GPI-anchor of PrPC by the Thy-1 GPI-anchor in order to investigate the role of these signals in sorting of PrPC in MDCK cells. Cell surface biotinylation experiments and confocal microscopy showed that lack of one N-linked oligosaccharide leads to loss of polarized sorting of PrPC. Exchange of the PrPC GPI-anchor for the one of Thy-1 redirects PrPC to the apical membrane. In conclusion, both N-glycosylation and GPI-anchor act on polarized sorting of PrPC, with the GPI-anchor being dominant over N-glycans.
Analysis of Prion Strains by PrPSc Profiling in Sporadic Creutzfeldt–Jakob Disease
Gaby Schoch,Harald Seeger,Julien Bogousslavsky,Markus Tolnay,Robert Charles Janzer,Adriano Aguzzi,Markus Glatzel
PLOS Medicine , 2006, DOI: 10.1371/journal.pmed.0030014
Abstract: Background Prion diseases are a group of invariably fatal neurodegenerative disorders affecting humans and a wide range of mammals. An essential part of the infectious agent, termed the prion, is composed of an abnormal isoform (PrPSc) of a host-encoded normal cellular protein (PrPC). The conversion of PrPC to PrPSc is thought to play a crucial role in the development of prion diseases and leads to PrPSc deposition, mainly in the central nervous system. Sporadic Creutzfeldt–Jakob disease (sCJD), the most common form of human prion disease, presents with a marked clinical heterogeneity. This diversity is accompanied by a molecular signature which can be defined by histological, biochemical, and genetic means. The molecular classification of sCJD is an important tool to aid in the understanding of underlying disease mechanisms and the development of therapy protocols. Comparability of classifications is hampered by disparity of applied methods and inter-observer variability. Methods and Findings To overcome these difficulties, we developed a new quantification protocol for PrPSc by using internal standards on each Western blot, which allows for generation and direct comparison of individual PrPSc profiles. By studying PrPSc profiles and PrPSc type expression within nine defined central nervous system areas of 50 patients with sCJD, we were able to show distinct PrPSc distribution patterns in diverse subtypes of sCJD. Furthermore, we were able to demonstrate the co-existence of more than one PrPSc type in individuals with sCJD in about 20% of all patients and in more than 50% of patients heterozygous for a polymorphism on codon 129 of the gene encoding the prion protein (PRNP). Conclusion PrPSc profiling represents a valuable tool for the molecular classification of human prion diseases and has important implications for their diagnosis by brain biopsy. Our results show that the co-existence of more than one PrPSc type might be influenced by genetic and brain region–specific determinants. These findings provide valuable insights into the generation of distinct PrPSc types.
Efficient Chemotherapy of Rat Glioblastoma Using Doxorubicin-Loaded PLGA Nanoparticles with Different Stabilizers
Stefanie Wohlfart,Alexander S. Khalansky,Svetlana Gelperina,Olga Maksimenko,Christian Bernreuther,Markus Glatzel,J?rg Kreuter
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019121
Abstract: Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB) prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods.
Amyloid-Precursor-Protein-Lowering Small Molecules for Disease Modifying Therapy of Alzheimer's Disease
Sina Cathérine Rosenkranz, Markus Geissen, Kristina H?rter, Beata Szalay, Isidro Ferrer, Jana Vogel, Stephen Smith, Markus Glatzel
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082255
Abstract: Alzheimer's disease (AD) is the most common form of dementia in the elderly with progressive cognitive decline and memory loss. According to the amyloid-hypothesis, AD is caused by generation and subsequent cerebral deposition of β-amyloid (Aβ). Aβ is generated through sequential cleavage of the transmembrane Amyloid-Precursor-Protein (APP) by two endoproteinases termed beta- and gamma-secretase. Increased APP-expression caused by APP gene dosage effects is a risk factor for the development of AD. Here we carried out a large scale screen for novel compounds aimed at decreasing APP-expression. For this we developed a screening system employing a cell culture model of AD. A total of 10,000 substances selected for their ability of drug-likeness and chemical diversity were tested for their potential to decrease APP-expression resulting in reduced Aβ-levels. Positive compounds were further evaluated for their effect at lower concentrations, absence of cytotoxicity and specificity. The six most promising compounds were characterized and structure function relationships were established. The novel compounds presented here provide valuable information for the development of causal therapies for AD.
A case-control study of sporadic Creutzfeldt-Jakob disease in Switzerland: analysis of potential risk factors with regard to an increased CJD incidence in the years 2001–2004
Jessica Ruegger, Katharina Stoeck, Lorenz Amsler, Thomas Blaettler, Marcel Zwahlen, Adriano Aguzzi, Markus Glatzel, Klaus Hess, Tobias Eckert
BMC Public Health , 2009, DOI: 10.1186/1471-2458-9-18
Abstract: To analyse potential risk factors for sCJD in Switzerland, close relatives of 69 sCJD-patients and 224 frequency age-matched controls were interviewed in a case-control study using a standardised questionnaire. 135 potential risk factors including socio-demographics, medical history, occupation and diet were analysed by logistic regression adjusting for age, sex and education.sCJD patients were more likely to have travelled abroad, worked at an animal laboratory, undergone invasive dental treatment, orthopaedic surgery, ophthalmologic surgery after 1980, regular GP visits, taken medication regularly, and consumed kidney. No differences between patients and controls were found for residency, family history, and exposure to environmental and other dietary factors.Although some factors were significantly more frequent among sCJD-cases, this study did not reveal specific explanations for the increased incidence of deaths due to sporadic CJD observed in Switzerland since 2001. Results have to be interpreted with caution due to multiple testing and possible recall bias in association with a long incubation period. The most plausible reason for the increase in Swiss sCJD cases after 2000 is an improved case ascertainment. Therefore, underreporting of cases might well have occurred before the year 2001, and the "real" yearly incidence of sCJD might not be lower than, but rather above 2 per million inhabitants.Creutzfeldt-Jakob disease (CJD) is a rare but inevitably fatal neurological disorder. CJD is associated with spongiform changes in the brain and an accumulation of a misfolded protein termed prion, which is believed to be the agent responsible for transmission of the disease.[1] In most industrialised countries, CJD is recorded with a yearly incidence of 1.0–1.5 cases per million inhabitants.[2] There are several pathogenically distinct forms of CJD, of which the classical forms (sporadic, genetic and iatrogenic) have been known for decades. Another form, variant CJD (
Deficiency in Serine Protease Inhibitor Neuroserpin Exacerbates Ischemic Brain Injury by Increased Postischemic Inflammation
Mathias Gelderblom, Melanie Neumann, Peter Ludewig, Christian Bernreuther, Susanne Krasemann, Priyadharshini Arunachalam, Christian Gerloff, Markus Glatzel, Tim Magnus
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063118
Abstract: The only approved pharmacological treatment for ischemic stroke is intravenous administration of plasminogen activator (tPA) to re-canalize the occluded cerebral vessel. Not only reperfusion but also tPA itself can induce an inflammatory response. Microglia are the innate immune cells of the central nervous system and the first immune cells to become activated in stroke. Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia. To examine neuroserpin-dependent mechanisms of neuroprotection in stroke, we studied neuroserpin deficient (Ns?/?) mice in an animal model of temporal focal ischemic stroke. Infarct size and neurological outcome were worse in neuroserpin deficient mice even though the fibrinolytic activity in the ischemic brain was increased. The increased infarct size was paralleled by a selective increase in proinflammatory microglia activation in Ns?/? mice. Our results show excessive microglial activation in Ns?/? mice mediated by an increased activity of tPA. This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA.
Dissemination of Orientia tsutsugamushi and Inflammatory Responses in a Murine Model of Scrub Typhus
Christian A. Keller equal contributor ,Matthias Hauptmann equal contributor,Julia Kolbaum,Mohammad Gharaibeh,Melanie Neumann,Markus Glatzel,Bernhard Fleischer
PLOS Neglected Tropical Diseases , 2014, DOI: 10.1371/journal.pntd.0003064
Abstract: Central aspects in the pathogenesis of scrub typhus, an infection caused by Orientia (O.) tsutsugamushi, have remained obscure. Its organ and cellular tropism are poorly understood. The purpose of this study was to analyze the kinetics of bacterial dissemination and associated inflammatory responses in infected tissues in an experimental scrub typhus mouse model, following infection with the human pathogenic strain Karp. We provide a thorough analysis of O. tsutsugamushi infection in inbred Balb/c mice using footpad inoculation, which is close to the natural way of infection. By a novel, highly sensitive qPCR targeting the multi copy traD genes, we quantitatively monitored the spread of O. tsutsugamushi Karp from the skin inoculation site via the regional lymph node to the internal target organs. The highest bacterial loads were measured in the lung. Using confocal imaging, we also detected O. tsutsugamushi at the single cell level in the lung and found a predominant macrophage rather than endothelial localization. Immunohistochemical analysis of infiltrates in lung and brain revealed differently composed lesions with specific localizations: iNOS-expressing macrophages were frequent in infiltrative parenchymal noduli, but uncommon in perivascular lesions within these organs. Quantitative analysis of the macrophage response by immunohistochemistry in liver, heart, lung and brain demonstrated an early onset of macrophage activation in the liver. Serum levels of interferon (IFN)-γ were increased during the acute infection, and we showed that IFN-γ contributed to iNOS-dependent bacterial growth control. Our data show that upon inoculation to the skin, O. tsutsugamushi spreads systemically to a large number of organs and gives rise to organ-specific inflammation patterns. The findings suggest an essential role for the lung in the pathogenesis of scrub typhus. The model will allow detailed studies on host-pathogen interaction and provide further insight into the pathogenesis of O. tsutsugamushi infection.
Preclinical Deposition of Pathological Prion Protein in Muscle of Experimentally Infected Primates
Susanne Krasemann,Melanie Neumann,Markus Geissen,Walter Bodemer,Franz-Josef Kaup,Walter Schulz-Schaeffer,Nathalie Morel,Adriano Aguzzi,Markus Glatzel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013906
Abstract: Prion diseases are transmissible fatal neurodegenerative disorders affecting humans and animals. A central step in disease progression is the accumulation of a misfolded form (PrPSc) of the host encoded prion protein (PrPC) in neuronal and non-neuronal tissues. The involvement of peripheral tissues in preclinical states increases the risk of accidental transmission. On the other hand, detection of PrPSc in non-neuronal easy-accessible compartments such as muscle may offer a novel diagnostic tool. Primate models have proven invaluable to investigate prion diseases. We have studied the deposition of PrPSc in muscle and central nervous system of rhesus monkeys challenged with sporadic Creutzfeldt-Jakob disease (sCJD), variant CJD (vCJD) and bovine spongiform encephalopathy (BSE) in preclinical and clinical stage using biochemical and morphological methods. Here, we show the preclinical presence of PrPSc in muscle and central nervous system of rhesus monkeys experimentally infected with vCJD.
Induced Prion Protein Controls Immune-Activated Retroviruses in the Mouse Spleen
Marius L?tscher, Mike Recher, Karl S. Lang, Alexander Navarini, Lukas Hunziker, Roger Santimaria, Markus Glatzel, Petra Schwarz, Jürg B?ni, Rolf M. Zinkernagel
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0001158
Abstract: The prion protein (PrP) is crucially involved in transmissible spongiform encephalopathies (TSE), but neither its exact role in disease nor its physiological function are known. Here we show for mice, using histological, immunochemical and PCR-based methods, that stimulation of innate resistance was followed by appearance of numerous endogenous retroviruses and ensuing PrP up-regulation in germinal centers of the spleen. Subsequently, the activated retroviruses disappeared in a PrP-dependent manner. Our results reveal the regular involvement of endogenous retroviruses in murine immune responses and provide evidence for an essential function of PrP in the control of the retroviral activity. The interaction between PrP and ubiquitous endogenous retroviruses may allow new interpretations of TSE pathophysiology and explain the evolutionary conservation of PrP.
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