Bonn, Germany

The German Center for Neurodegenerative Diseases aims to develop new preventive and therapeutic approaches for neurodegenerative diseases. To accomplish this the DZNE follows a translational approach. This means that fundamental research is closely related to clinical research, population studies and health care research. In total there are nine sites all over Germany: Berlin, Bonn, Dresden, Göttingen, Magdeburg, Munich, Rostock / Greifswald, Tübingen and Witten. At each site the DZNE works closely with universities, university hospitals and other partners.The DZNE receives 90 percent of its funding from the Federal Ministry of Education and Research and 10 percent from the respective federal states containing DZNE sites. Wikipedia.


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Ground-breaking study opens up new area of preventative research for diseases like Alzheimer's: Targeting age-dependent protein aggregates as possible therapeutic targets In a recent Frontiers in Aging Neuroscience paper, Drs. Della David and Frank Baumann together with their teams at the German Center for Neurodegenerative Diseases and Hertie Institute, showed that changes in proteins associated with aging were directly implicated in the protein formations commonly associated with Alzheimer's disease. Neurodegenerative diseases are often associated with protein aggregates. These are clumps of proteins created when misfolded proteins - proteins that have lost the elaborate but recognizable shape that dictates their function - assemble together to form a highly intractable structure. Recent research has also shown that even in the absence of disease, proteins can aggregate increasingly with age. In the case of Alzheimer's the researchers investigated whether the Amyloid beta (Aβ) aggregates closely associated with the disease could be induced by aging seeds: proteins that clump together with age to form aggregates. This would occur through a hypothesized phenomenon called cross-seeding, where different protein aggregates can induce each other's aggregation. Crucially, the few existing examples of cross-seeding occur between disease-associated proteins. The study's experiments on C. elegans, an organism whose limited number of cells and relative complexity makes it an ideal test subject, showed that age-dependent protein aggregates can induce Aβ aggregation in vitro, and that the age-dependent protein aggregates of older C. elegans specimens were particularly likely to cross-seed Aβ aggregates. In order to verify the applicability of these results to mammals, the same tests were performed in vitro on mouse brain extracts of varying age, with similar outcomes. By performing a protein count via mass spectrometry for C. elegans, the study also identified some proteins for further investigation. The most promising candidates for cross-seeding activity were proteins present as minor components in disease-associated aggregates, which aggregate increasingly after middle-age. Furthermore, the researchers demonstrated that one of these aggregation-prone proteins, PAR-5, can induce Aβ toxicity in vivo. According to paralysis rates, the combination of overexpressed PAR-5 with overexpressed Aβ accelerated Aβ toxicity in C. elegans. Combined with the mass spectrometry, these experiments further highlight that certain minor components may qualify as proteins that "could be more prone to aggregate in specific brain regions and thus help the generation and spreading of disease-associated seeds in certain brain circuits." This study thus predicts that changes in protein conformations associated with old age may initiate Alzheimer's disease through Aβ aggregation and toxicity. Given that the study's in vitro assays cannot mimic the entire complexity of the brain and picture all neurobiological interactions, the researchers encourage an "in vivo assessment by injecting age-dependent aggregates into a pre-symptomatic transgenic mouse models for Alzheimer's disease." They add that aggregating proteins should be mapped in both healthy and neurodegenerative human brain samples, as a way of clarifying "which aging seeds need to be looked at and whether certain aging seeds would be more prone to seed or associate with specific disease types in specific anatomical areas." This research is part of a broader collection of articles - a Frontiers Research Topic - which elucidates on the mechanisms of protein folding and their role in neurodegenerative disorders.


News Article | May 19, 2017
Site: www.eurekalert.org

A study led by the University of Bonn opens a new perspective with regard to the development of dementia. The scientists blocked the breakdown of a certain fat molecule in the mouse brain. As a result the animals exhibited learning and memory problems. Also the quantity of Alzheimer-specific proteins in their brains increased significantly. The researchers now have a clue as to why the mice become dumb. The results are published in the renowned scientific journal "Autophagy". Apart from water, our brain is rich in lipids -- in plain language: fats. The lipids act, for instance, as an insulating layer around the nerve fibers and thus prevent short circuits. However, they are also a main component in the delicate membranes that surround the brain cells. Sphingolipids, a special lipid type are highly enriched in the brain. One of their degradation products, S1P, may play a central role in the development of Alzheimer's and other forms of dementia. "We raised mice that are no longer able to break down S1P in large parts of their brain," explains Dr. Gerhild van Echten-Deckert. "The animals then displayed severely reduced learning and memory performance." Van Echten-Deckert undertakes research at the LIMES Institute at the University of Bonn (the acronym stands for "Life and Medical Sciences") as an assistant professor. For a long time, she has been one of the few experts in the world interested in the role of S1P in the brain. The new study could fundamentally change this, as the researchers at the University of Bonn, Jena University Hospital, the German Center for Neurodegenerative Diseases (DZNE) and from San Francisco and Madrid were able to show what far-reaching consequences disrupted S1P breakdown has. Normally, S1P is broken down into simpler products. One such breakdown product generated is important for a vital metabolic pathway - called autophagy. The word autophagy (literally translates to "self-eating") and the pathway enables cells to digest and recycle their own components. The cells are thus cleared from defective proteins and cell organelles that no longer function properly. Intracellular waste disposal works in two steps: first, it packs the waste in tiny "garbage bags". These then merge with other "bags" that contain highly reactive enzymes. The enzymes "shred" the content of the garbage bags and thus dispose it off. The break-down product of S1P is involved in packing the waste into the intracellular garbage bags. "If S1P is not broken down, fewer closed garbage bags are formed; autophagy then no longer works accurately," explains the first author of the study Daniel Mitroi, who has recently completed his PhD at the LIMES Institute. "Harmful substances thus accumulated in the brains of our mice. These included the protein APP, which plays a key role in the development of Alzheimer's." As autophagy is crucial for normal functioning of the brain, improper intracellular waste disposal results in severe illnesses. Therefore last year the Nobel Prize in Medicine was awarded to the Japanese scientist Yoshinori Ohsumi for his notable work on this vital mechanism. The results of the current study shed light on a previously overlooked mechanism for dementia development. "In the long term, our work may contribute towards developing successful treatment strategies for brain disorders," hopes Dr. van Echten-Deckert.


In a recent Frontiers in Aging Neuroscience paper, Drs. Della David and Frank Baumann together with their teams at the German Center for Neurodegenerative Diseases and Hertie Institute, showed that changes in proteins associated with aging were directly implicated in the protein formations commonly associated with Alzheimer's disease. Neurodegenerative diseases are often associated with protein aggregates. These are clumps of proteins created when misfolded proteins -- proteins that have lost the elaborate but recognizable shape that dictates their function -- assemble together to form a highly intractable structure. Recent research has also shown that even in the absence of disease, proteins can aggregate increasingly with age. In the case of Alzheimer's the researchers investigated whether the Amyloid beta (A?) aggregates closely associated with the disease could be induced by aging seeds: proteins that clump together with age to form aggregates. This would occur through a hypothesized phenomenon called cross-seeding, where different protein aggregates can induce each other's aggregation. Crucially, the few existing examples of cross-seeding occur between disease-associated proteins. The study's experiments on C. elegans, an organism whose limited number of cells and relative complexity makes it an ideal test subject, showed that age-dependent protein aggregates can induce A? aggregation in vitro, and that the age-dependent protein aggregates of older C. elegans specimens were particularly likely to cross-seed A? aggregates. In order to verify the applicability of these results to mammals, the same tests were performed in vitro on mouse brain extracts of varying age, with similar outcomes. By performing a protein count via mass spectrometry for C. elegans, the study also identified some proteins for further investigation. The most promising candidates for cross-seeding activity were proteins present as minor components in disease-associated aggregates, which aggregate increasingly after middle-age. Furthermore, the researchers demonstrated that one of these aggregation-prone proteins, PAR-5, can induce A? toxicity in vivo. According to paralysis rates, the combination of overexpressed PAR-5 with overexpressed A? accelerated A? toxicity in C. elegans. Combined with the mass spectrometry, these experiments further highlight that certain minor components may qualify as proteins that "could be more prone to aggregate in specific brain regions and thus help the generation and spreading of disease-associated seeds in certain brain circuits." This study thus predicts that changes in protein conformations associated with old age may initiate Alzheimer's disease through A? aggregation and toxicity. Given that the study's in vitro assays cannot mimic the entire complexity of the brain and picture all neurobiological interactions, the researchers encourage an "in vivo assessment by injecting age-dependent aggregates into a pre-symptomatic transgenic mouse models for Alzheimer's disease." They add that aggregating proteins should be mapped in both healthy and neurodegenerative human brain samples, as a way of clarifying "which aging seeds need to be looked at and whether certain aging seeds would be more prone to seed or associate with specific disease types in specific anatomical areas."


News Article | May 19, 2017
Site: www.sciencedaily.com

A study led by the University of Bonn opens a new perspective with regard to the development of dementia. The scientists blocked the breakdown of a certain fat molecule in the mouse brain. As a result the animals exhibited learning and memory problems. Also the quantity of Alzheimer-specific proteins in their brains increased significantly. The researchers now have a clue as to why the mice become dumb. The results are published in the scientific journal Autophagy. Apart from water, our brain is rich in lipids -- in plain language: fats. The lipids act, for instance, as an insulating layer around the nerve fibers and thus prevent short circuits. However, they are also a main component in the delicate membranes that surround the brain cells. Sphingolipids, a special lipid type are highly enriched in the brain. One of their degradation products, S1P, may play a central role in the development of Alzheimer's and other forms of dementia. "We raised mice that are no longer able to break down S1P in large parts of their brain," explains Dr. Gerhild van Echten-Deckert. "The animals then displayed severely reduced learning and memory performance." Van Echten-Deckert undertakes research at the LIMES Institute at the University of Bonn (the acronym stands for "Life and Medical Sciences") as an assistant professor. For a long time, she has been one of the few experts in the world interested in the role of S1P in the brain. The new study could fundamentally change this, as the researchers at the University of Bonn, Jena University Hospital, the German Center for Neurodegenerative Diseases (DZNE) and from San Francisco and Madrid were able to show what far-reaching consequences disrupted S1P breakdown has. Normally, S1P is broken down into simpler products. One such breakdown product generated is important for a vital metabolic pathway -- called autophagy. The word autophagy (literally translates to "self-eating") and the pathway enables cells to digest and recycle their own components. The cells are thus cleared from defective proteins and cell organelles that no longer function properly. Intracellular waste disposal works in two steps: first, it packs the waste in tiny "garbage bags." These then merge with other "bags" that contain highly reactive enzymes. The enzymes "shred" the content of the garbage bags and thus dispose it off. The break-down product of S1P is involved in packing the waste into the intracellular garbage bags. "If S1P is not broken down, fewer closed garbage bags are formed; autophagy then no longer works accurately," explains the first author of the study Daniel Mitroi, who has recently completed his PhD at the LIMES Institute. "Harmful substances thus accumulated in the brains of our mice. These included the protein APP, which plays a key role in the development of Alzheimer's." As autophagy is crucial for normal functioning of the brain, improper intracellular waste disposal results in severe illnesses. Therefore last year the Nobel Prize in Medicine was awarded to the Japanese scientist Yoshinori Ohsumi for his notable work on this vital mechanism. The results of the current study shed light on a previously overlooked mechanism for dementia development. "In the long term, our work may contribute towards developing successful treatment strategies for brain disorders," hopes Dr. van Echten-Deckert.


News Article | May 5, 2017
Site: www.eurekalert.org

Dendritic cells are gatekeepers of Immunity and are crucial for the detection and initiation of Immunity against pathogens and foreign substances. Up to now dendritic cell subtypes were thought to develop from one common progenitor. Now, in a joint effort, researchers from A*STAR Singapore Immunology Network, LIMES-Institute and cluster of excellence ImmunoSensation from University of Bonn and the German Center for Neurodegenerative Diseases were able to show with single cell resolution that this important component of the human immune system develops from specialized progenitors. These findings are now published in Science and have implications for the development and optimization of vaccines. "Our blood is more than just red blood cells, which are important for oxygen transport", Dr. Andreas Schlitzer of the University of Bonn states. "It's full of a variety of Immune cells which are crucial for the defence against pathogens such as bacteria or viruses". Researchers have been dissecting the blood immune cell compartment for a long time. Human dendritic cells in the blood are an important interface between the innate and the adaptive branch of the immune system. Thereby these results constitute an important step in understanding the role of this immune cell subtype during the regulation of human immune responses. How are these processes regulated? "Up to know assessing the transcriptional regulation of single human dendritic cells was extremely difficult", Dr. Schlitzer reports. However now the research teams from Singapore and the University of Bonn were able to analyse these processes with a combination of single cell transcriptomics, Mass Cytometry and sophisticated high-dimensional flow cytometry, which allowed unprecedented detail to fully understand the development of these immune cells. The research team, led by Dr Florent Ginhoux from A*STAR's Singapore Immunology Network (SigN) in collaboration with Prof. Dr. Joachim Schultze, Dr. Andreas Schlitzer and Dr. Marc Beyer from the Life & Medical Sciences Institute (LIMES) of the University of Bonn and the German Center for Neurodegenerative Diseases were now able to analyse the regulation of human dendritic cell development and functional specialization with single cell resolution in the human blood and bone marrow. During the analysis of the complete developmental cycle of these dendritic cells the researcher made a remarkable finding. Previously it was thought that dendritic cell subtypes derive from one common progenitor, however this dogma has been overthrown by these recent data. Here, the researchers could show that dendritic cells, rather than developing from one common progenitor, are developing from subtype specialised progenitors which find their subtype identity already very early during their development in the human bone marrow. These findings provide the basis for a better and more detailed understanding of the regulation of human immune response and are important for the development of new and more effective vaccinations against e.g. infectious diseases. Publication: Mapping the human DC lineage through the integration of high-dimensional techniques, Science, DOI: 10.1126/science.aag3009


Fischer A.,University of Gottingen | Fischer A.,German Center for Neurodegenerative Diseases
EMBO Journal | Year: 2014

Recent data support the view that epigenetic processes play a role in memory consolidation and help to transmit acquired memories even across generations in a Lamarckian manner. Drugs that target the epigenetic machinery were found to enhance memory function in rodents and ameliorate disease phenotypes in models for brain diseases such as Alzheimer's disease, Chorea Huntington, Depression or Schizophrenia. In this review, I will give an overview on the current knowledge of epigenetic processes in memory function and brain disease with a focus on Morbus Alzheimer as the most common neurodegenerative disease. I will address the question whether an epigenetic therapy could indeed be a suitable therapeutic avenue to treat brain diseases and discuss the necessary steps that should help to take neuroepigenetic research to the next level. As part of our review series on Molecular Memory, Andre Fischer discusses epigenetic processes leading to memory formation and transgenerational inheritance under physiological and pathological conditions such as Alzheimer's disease. © 2014 The Author. Published under the terms of the CC BY NC ND license.


Eisenberg D.,Howard Hughes Medical Institute | Jucker M.,University of Tübingen | Jucker M.,German Center for Neurodegenerative Diseases
Cell | Year: 2012

Amyloid fibers and oligomers are associated with a great variety of human diseases including Alzheimer's disease and the prion conditions. Here we attempt to connect recent discoveries on the molecular properties of proteins in the amyloid state with observations about pathological tissues and disease states. We summarize studies of structure and nucleation of amyloid and relate these to observations on amyloid polymorphism, prion strains, coaggregation of pathogenic proteins in tissues, and mechanisms of toxicity and transmissibility. Molecular studies have also led to numerous strategies for biological and chemical interventions against amyloid diseases. © 2012 Elsevier Inc.


Ulusoy A.,German Center for Neurodegenerative Diseases
Molecular neurobiology | Year: 2013

The discovery of α-synuclein has had profound implications concerning our understanding of Parkinson's disease (PD) and other neurodegenerative disorders characterized by α-synuclein accumulation. In fact, as compared with pre-α-synuclein times, a "new" PD can now be described as a whole-body disease in which a progressive spreading of α-synuclein pathology underlies a wide spectrum of motor as well as nonmotor clinical manifestations. Not only is α-synuclein accumulation a pathological hallmark of human α-synucleinopathies but increased protein levels are sufficient to trigger neurodegenerative processes. α-Synuclein elevations could also be a mechanism by which disease risk factors (e.g., aging) increase neuronal vulnerability to degeneration. An important corollary to the role of enhanced α-synuclein in PD pathogenesis is the possibility of developing α-synuclein-based biomarkers and new therapeutics aimed at suppressing α-synuclein expression. The use of in vitro and in vivo experimental models, including transgenic mice overexpressing α-synuclein and animals with viral vector-mediated α-synuclein transduction, has helped clarify pathogenetic mechanisms and therapeutic strategies involving α-synuclein. These models are not devoid of significant limitations, however. Therefore, further pursuit of new clues on the cause and treatment of PD in this post-α-synuclein era would benefit substantially from the development of improved research paradigms of α-synuclein elevation.


Jackson W.S.,German Center for Neurodegenerative Diseases
DMM Disease Models and Mechanisms | Year: 2014

The mechanisms underlying the selective targeting of specific brain regions by different neurodegenerative diseases is one of the most intriguing mysteries in medicine. For example, it is known that Alzheimer's disease primarily affects parts of the brain that play a role in memory, whereas Parkinson's disease predominantly affects parts of the brain that are involved in body movement. However, the reasons that other brain regions remain unaffected in these diseases are unknown. A better understanding of the phenomenon of selective vulnerability is required for the development of targeted therapeutic approaches that specifically protect affected neurons, thereby altering the disease course and preventing its progression. Prion diseases are a fascinating group of neurodegenerative diseases because they exhibit a wide phenotypic spectrum caused by different sequence perturbations in a single protein. The possible ways that mutations affecting this protein can cause several distinct neurodegenerative diseases are explored in this Review to highlight the complexity underlying selective vulnerability. The premise of this article is that selective vulnerability is determined by the interaction of specific protein conformers and region-specific microenvironments harboring unique combinations of subcellular components such as metals, chaperones and protein translation machinery. Given the abundance of potential contributory factors in the neurodegenerative process, a better understanding of how these factors interact will provide invaluable insight into disease mechanisms to guide therapeutic discovery. © 2014. Published by The Company of Biologists Ltd.


Kempermann G.,German Center for Neurodegenerative Diseases
Cell | Year: 2014

In the adult brain, new neurons are produced in two "canonical" regions: the hippocampus and the olfactory bulb. Ernst et al. now show that, unlike other species, humans also display robust neurogenesis in the striatum, an unexpected finding with important physiological, pathological, and evolutionary implications. © 2014 Elsevier Inc.

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