Kügler, Sebastian

[["dc.bibliographiccitation.journal","International journal of Alzheimer's disease"],["dc.bibliographiccitation.volume","2010"],["dc.contributor.author","Jaworski, Tomasz"],["dc.contributor.author","Kügler, Sebastian"],["dc.contributor.author","Van Leuven, Fred"],["dc.date.accessioned","2019-07-09T11:53:09Z"],["dc.date.available","2019-07-09T11:53:09Z"],["dc.date.issued","2010"],["dc.description.abstract","Patients suffering from Alzheimer's disease (AD) are typified and diagnosed postmortem by the combined accumulations of extracellular amyloid plaques and of intracellular tauopathy, consisting of neuropil treads and neurofibrillary tangles in the somata. Both hallmarks are inseparable and remain diagnostic as described by Alois Alzheimer more than a century ago. Nevertheless, these pathological features are largely abandoned as being the actual pathogenic or neurotoxic factors. The previous, almost exclusive experimental attention on amyloid has shifted over the last 10 years in two directions. Firstly, from the \"concrete\" deposits of amyloid plaques to less well-defined soluble or pseudosoluble oligomers of the amyloid peptides, ranging from dimers to dodecamers and even larger aggregates. A second shift in research focus is from amyloid to tauopathy, and to their mutual relation. The role of Tau in the pathogenesis and disease progression is appreciated as leading to synaptic and neuronal loss, causing cognitive deficits and dementia. Both trends are incorporated in a modified amyloid cascade hypothesis, briefly discussed in this paper that is mainly concerned with the second aspect, that is, protein Tau and its associated fundamental questions."],["dc.identifier.doi","10.4061/2010/573138"],["dc.identifier.fs","577408"],["dc.identifier.pmid","20862366"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6921"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/60351"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","2090-0252"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","610"],["dc.title","Modeling of tau-mediated synaptic and neuronal degeneration in Alzheimer's disease."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e7280"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","PloS one"],["dc.bibliographiccitation.volume","4"],["dc.contributor.author","Jaworski, Tomasz"],["dc.contributor.author","Dewachter, Ilse"],["dc.contributor.author","Lechat, Benoit"],["dc.contributor.author","Croes, Sophie"],["dc.contributor.author","Termont, Annelies"],["dc.contributor.author","Demedts, David"],["dc.contributor.author","Borghgraef, Peter"],["dc.contributor.author","Devijver, Herman"],["dc.contributor.author","Filipkowski, Robert K."],["dc.contributor.author","Kaczmarek, Leszek"],["dc.contributor.author","Kügler, Sebastian"],["dc.contributor.author","Van Leuven, Fred"],["dc.date.accessioned","2019-07-09T11:52:41Z"],["dc.date.available","2019-07-09T11:52:41Z"],["dc.date.issued","2009"],["dc.description.abstract","In Alzheimer's disease tauopathy is considered secondary to amyloid, and the duality obscures their relation and the definition of their respective contributions.Transgenic mouse models do not resolve this problem conclusively, i.e. the relative hierarchy of amyloid and tau pathology depends on the actual model and the genes expressed or inactivated. Here, we approached the problem in non-transgenic models by intracerebral injection of adeno-associated viral vectors to express protein tau or amyloid precursor protein in the hippocampus in vivo. AAV-APP mutant caused neuronal accumulation of amyloid peptides, and eventually amyloid plaques at 6 months post-injection, but with only marginal hippocampal cell-death. In contrast, AAV-Tau, either wild-type or mutant P301L, provoked dramatic degeneration of pyramidal neurons in CA1/2 and cortex within weeks. Tau-mediated neurodegeneration proceeded without formation of large fibrillar tau-aggregates or tangles, but with increased expression of cell-cycle markers.We present novel AAV-based models, which demonstrate that protein tau mediates pyramidal neurodegeneration in vivo. The data firmly support the unifying hypothesis that post-mitotic neurons are forced to re-enter the cell-cycle in primary and secondary tauopathies, including Alzheimer's disease."],["dc.format.extent","16"],["dc.identifier.doi","10.1371/journal.pone.0007280"],["dc.identifier.fs","568159"],["dc.identifier.pmid","19794916"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/5823"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/60252"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/020589"],["dc.relation.euproject","EURON"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 2.5"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.5"],["dc.subject.ddc","610"],["dc.title","AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","49"],["dc.bibliographiccitation.journal","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Tolö, Johan"],["dc.contributor.author","Taschenberger, Grit"],["dc.contributor.author","Leite, Kristian"],["dc.contributor.author","Stahlberg, Markus A."],["dc.contributor.author","Spehlbrink, Gesche"],["dc.contributor.author","Kues, Janina"],["dc.contributor.author","Munari, Francesca"],["dc.contributor.author","Capaldi, Stefano"],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Dean, Camin"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Kügler, Sebastian"],["dc.date.accessioned","2019-07-09T11:45:10Z"],["dc.date.available","2019-07-09T11:45:10Z"],["dc.date.issued","2018"],["dc.description.abstract","α-Synuclein (α-Syn) is intimately linked to the etiology of Parkinson's Disease, as mutations and even subtle increases in gene dosage result in early onset of the disease. However, how this protein causes neuronal dysfunction and neurodegeneration is incompletely understood. We thus examined a comprehensive range of physiological parameters in cultured rat primary neurons overexpressing α-Syn at levels causing a slowly progressive neurodegeneration. In contradiction to earlier reports from non-neuronal assay systems we demonstrate that α-Syn does not interfere with essential ion handling capacities, mitochondrial capability of ATP production or basic electro-physiological properties like resting membrane potential or the general ability to generate action potentials. α-Syn also does not activate canonical stress kinase Signaling converging on SAPK/Jun, p38 MAPK or Erk kinases. Causative for α-Syn-induced neurodegeneration are mitochondrial thiol oxidation and activation of caspases downstream of mitochondrial outer membrane permeabilization, leading to apoptosis-like cell death execution with some unusual aspects. We also aimed to elucidate neuroprotective strategies counteracting the pathophysiological processes caused by α-Syn. Neurotrophic factors, calpain inhibition and increased lysosomal protease capacity showed no protective effects against α-Syn overexpression. In contrast, the major watchdog of outer mitochondrial membrane integrity, Bcl-Xl, was capable of almost completely preventing neuron death, but did not prevent mitochondrial thiol oxidation. Importantly, independent from the quite mono-causal induction of neurotoxicity, α-Syn causes diminished excitability of neurons by external stimuli and robust impairments in endogenous neuronal network activity by decreasing the frequency of action potentials generated without external stimulation. This latter finding suggests that α-Syn can induce neuronal dysfunction independent from its induction of neurotoxicity and might serve as an explanation for functional deficits that precede neuronal cell loss in synucleopathies like Parkinson's disease or dementia with Lewy bodies."],["dc.identifier.doi","10.3389/fnmol.2018.00049"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15047"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59171"],["dc.language.iso","en"],["dc.notes.intern","DeepGreen Import"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1662-5099"],["dc.relation.issn","1662-5099"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.subject.ddc","610"],["dc.title","Pathophysiological Consequences of Neuronal α-Synuclein Overexpression: Impacts on Ion Homeostasis, Stress Signaling, Mitochondrial Integrity, and Electrical Activity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]