Deutsches Zentrum fur Neurodegenerative Erkrankungen DZNE e.V.

Witten, Germany

Deutsches Zentrum fur Neurodegenerative Erkrankungen DZNE e.V.

Witten, Germany
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Osterbrink J.,Paracelsus Medical University | Hufnagel M.,Paracelsus Medical University | Kutschar P.,Paracelsus Medical University | Mitterlehner B.,Paracelsus Medical University | And 8 more authors.
Schmerz | Year: 2012

Background: Little is known about the phenomenon of pain in German nursing homes. In particular, it is unknown to what extent and severity pain occurs among residents and how their pain can be described. Material and methods: A total of 13 nursing homes located in the city of Münster, Germany, were included as part of the health services research project "Action Alliance Pain-free City Münster." Data were collected from 436 residents over 65 years old via self-report or the observational pain tool pain assessment in advanced dementia, german version (PAINAD-G), according to the cognitive status of the residents. Results: At the time of the interview, the majority of the residents questioned reported suffering from pain at rest and/or during movement. Approximately one quarter of residents complained about moderate to intolerable pain at rest and nearly 45% during movement. Residents encountered pain most often when standing up, sitting, resting in bed and walking and three quarters of residents had suffered from pain for more than 1 year. Many residents experienced pain in several body regions. Among residents assessed solely by the observational pain scale PAINAD-G, signs indicating pain existed in 21% (≥ 6) or 69% (≥ 2), respectively, depending on the cut-off value chosen on the PAINAD-G scale. Conclusion: Pain in nursing homes is a challenge that needs more attention as it has considerable negative consequences for the persons concerned. The extent of pain in the studied facilities indicates an urgent need for action on the part of all professionals caring for residents in nursing homes. © 2012 Springer-Verlag.


Wefers B.,Helmholtz Center for Environmental Research | Ortiz O.,Helmholtz Center for Environmental Research | Wurst W.,Helmholtz Center for Environmental Research | Wurst W.,TU Munich | And 4 more authors.
Methods | Year: 2014

Gene engineering for generating targeted mouse mutants is a key technology for biomedical research. Using TALENs as nucleases to induce targeted double-strand breaks, the mouse genome can be directly modified in zygotes in a single step, without the need for embryonic stem cells. Thereby, knockout and knockin alleles can be generated fast and efficiently by embryo microinjection of TALEN mRNAs and targeting vectors. In this article we present an introduction into the TALEN technology and provide protocols for the application of TALENs in mouse zygotes. © 2014 Elsevier Inc.


Brandl C.,Helmholtz Center for Environmental Research | Brandl C.,TU Munich | Ortiz O.,Helmholtz Center for Environmental Research | Rottig B.,Helmholtz Center for Environmental Research | And 10 more authors.
FEBS Open Bio | Year: 2015

The use of TALEN and CRISPR/CAS nucleases is becoming increasingly popular as a means to edit single target sites in one-cell mouse embryos. Nevertheless, an area that has received less attention concerns the engineering of structural genome variants and the necessary religation of two distant double-strand breaks. Herein, we applied pairs of TALEN or sgRNAs and Cas9 to create deletions in the Rab38 gene. We found that the deletion of 3.2 or 9.3. kb, but not of 30. kb, occurs at a frequency of 6-37%. This is sufficient for the direct production of mutants by embryo microinjection. Therefore, deletions up to ~10. kb can be readily achieved for modeling human disease alleles. This work represents an important step towards the establishment of new protocols that support the ligation of remote DSB ends to achieve even larger rearrangements. © 2014 The Authors.


Reuther S.,Deutsches Zentrum fur Neurodegenerative Erkrankungen e.V. DZNE | Reuther S.,Witten/Herdecke University | van Nie N.,Maastricht University | Meijers J.,Maastricht University | And 3 more authors.
Zeitschrift fur Gerontologie und Geriatrie | Year: 2013

Background and objective: Dementia is one of most challenging problems for the care of older people in Germany. Although malnutrition in nursing homes is also associated with dementia, few systematic studies have described health care structures in German nursing homes for people with dementia and their individual nutritional status. Therefore, the aim of this study was to determine dementia-specific differences concerning the nutrition situation for the elderly in German nursing homes. Methods: A cross-sectional multicenter study was performed using a standardized multilevel instrument (observation, questionnaire) developed at the University of Maastricht. Variables are indicators for malnutrition and its risks, quality indicators, care dependency and types of interventions. Results: In the 2008 and 2009 surveys, 53% of 4,777 participants (77. 9% women, 22. 1% men, mean age 82 years) were identified (based on care documentation) as having dementia. More than one third of this population (n = 759, 85. 1% women, 14. 1% men, mean age 85 years) was probably malnourished; thus, the prevalence rate in the group of people with dementia was 10% higher compared to the group without dementia. People with dementia showed a higher risk in all relevant risk indicators (weight history, body mass index, and food intake) for malnutrition compared to those without dementia. Furthermore, people with dementia had higher care dependency rates and required more assistance for eating and drinking. Conclusion: The study results confirm the relationship between malnutrition and dementia. The use of standardized nutrition screening tools is not common practice in German nursing homes yet. However, the results suggest that with an increasing risk for malnutrition combined with dementia the proportion of nursing interventions also increases, which means that nurses must react adequately. Nevertheless, the interventions concerning malnutrition should be improved especially with respect to preventive measurements. © 2012 Springer-Verlag Berlin Heidelberg.


Gewies A.,TU Munich | Gewies A.,German Cancer Research Center | Gorka O.,TU Munich | Bergmann H.,TU Munich | And 23 more authors.
Cell Reports | Year: 2014

The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-κB activation, and its proteolytic domain cleaves negative NF-κB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration invivo. Paracaspase activity is essential for regulatory Tcell (Treg) and innate-like B cell development, but it is largelydispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-κB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFNγ) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation. © 2014 The Authors.


Lange M.D.,University of Munster | Jungling K.,University of Munster | Paulukat L.,University of Munster | Vieler M.,University of Munster | And 7 more authors.
Neuropsychopharmacology | Year: 2014

An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABA B receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders. © 2014 American College of Neuropsychopharmacology. All rights reserved.


Runkel E.D.,Albert Ludwigs University of Freiburg | Liu S.,Albert Ludwigs University of Freiburg | Liu S.,Deutsches Zentrum fur Neurodegenerative Erkrankungen e.V. DZNE | Baumeister R.,Albert Ludwigs University of Freiburg | Schulze E.,Albert Ludwigs University of Freiburg
PLoS Genetics | Year: 2013

Disturbance of cellular functions results in the activation of stress-signaling pathways that aim at restoring homeostasis. We performed a genome-wide screen to identify components of the signal transduction of the mitochondrial unfolded protein response (UPRmt) to a nuclear chaperone promoter. We used the ROS generating complex I inhibitor paraquat to induce the UPRmt, and we employed RNAi exposure post-embryonically to allow testing genes whose knockdown results in embryonic lethality. We identified 54 novel regulators of the ROS-induced UPRmt. Activation of the UPRmt, but not of other stress-signaling pathways, failed when homeostasis of basic cellular mechanisms such as translation and protein transport were impaired. These mechanisms are monitored by a recently discovered surveillance system that interprets interruption of these processes as pathogen attack and depends on signaling through the JNK-like MAP-kinase KGB-1. Mutation of kgb-1 abrogated the inhibition of ROS-induced UPRmt, suggesting that surveillance-activated defenses specifically inhibit the UPRmt but do not compromise activation of the heat shock response, the UPR of the endoplasmic reticulum, or the SKN-1/Nrf2 mediated response to cytosolic stress. In addition, we identified PIFK-1, the orthologue of the Drosophila PI 4-kinase four wheel drive (FWD), and found that it is the only known factor so far that is essential for the unfolded protein responses of both mitochondria and endoplasmic reticulum. This suggests that both UPRs may share a common membrane associated mechanism. © 2013 Runkel et al.


Hettich M.M.,Deutsches Zentrum fur Neurodegenerative Erkrankungen E.V. DZNE | Matthes F.,Deutsches Zentrum fur Neurodegenerative Erkrankungen E.V. DZNE | Ryan D.P.,Deutsches Zentrum fur Neurodegenerative Erkrankungen E.V. DZNE | Griesche N.,Deutsches Zentrum fur Neurodegenerative Erkrankungen E.V. DZNE | And 4 more authors.
PLoS ONE | Year: 2014

Alzheimer's disease (AD), the most common form of dementia in the elderly, is characterized by two neuropathological hallmarks: senile plaques, which are composed of Aβ peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated TAU protein. Diabetic patients with dysregulated insulin signalling are at increased risk of developing AD. Further, several animal models of diabetes show increased Aβ expression and hyperphosphorylated tau. As we have shown recently, the anti-diabetic drug metformin is capable of dephosphorylating tau at AD-relevant phospho-sites. Here, we investigated the effect of metformin on the main amyloidogenic enzyme BACE1 and, thus, on the production of Aβ peptides, the second pathological hallmark of AD. We find similar results in cultures of primary neurons, a human cell line model of AD and in vivo in mice. We show that treatment with metformin decreases BACE1 protein expression by interfering with an mRNA-protein complex that contains the ubiquitin ligase MID1, thereby reducing BACE1 activity. Together with our previous findings these results indicate that metformin may target both pathological hallmarks of AD and may be of therapeutic value for treating and/or preventing AD. © 2014 Hettich et al.


PubMed | Deutsches Zentrum fur Neurodegenerative Erkrankungen e.V. DZNE
Type: Journal Article | Journal: PloS one | Year: 2014

Alzheimers disease (AD), the most common form of dementia in the elderly, is characterized by two neuropathological hallmarks: senile plaques, which are composed of A peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated TAU protein. Diabetic patients with dysregulated insulin signalling are at increased risk of developing AD. Further, several animal models of diabetes show increased A expression and hyperphosphorylated tau. As we have shown recently, the anti-diabetic drug metformin is capable of dephosphorylating tau at AD-relevant phospho-sites. Here, we investigated the effect of metformin on the main amyloidogenic enzyme BACE1 and, thus, on the production of A peptides, the second pathological hallmark of AD. We find similar results in cultures of primary neurons, a human cell line model of AD and in vivo in mice. We show that treatment with metformin decreases BACE1 protein expression by interfering with an mRNA-protein complex that contains the ubiquitin ligase MID1, thereby reducing BACE1 activity. Together with our previous findings these results indicate that metformin may target both pathological hallmarks of AD and may be of therapeutic value for treating and/or preventing AD.


PubMed | Deutsches Zentrum fur Neurodegenerative Erkrankungen DZNE e.V.
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2015

Combining density gradient centrifugation with magnetic cell sorting provides a powerful tool to isolate blood cells with high reproducibility, yield, and purity. It also allows for subsequent separation of multiple cell types, resulting in the possibility to analyze different purified fractions from one donors sample. The centrifugation step divides whole blood into peripheral blood mononuclear cells (PBMC), erythrocytes, and platelet-rich plasma. In the following, lymphocyte subtypes can be consecutively isolated from the PBMC fraction. This chapter describes enrichment of erythrocytes, CD14-positive monocytes and CD3-positive T lymphocytes. Alternatively, other cell types can be targeted by using magnetic beads specific for the desired subpopulation.

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