Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease
DC Element | Wert | Sprache |
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dc.contributor.author | Fath, Thomas | |
dc.contributor.author | Eidenmüller, Jochen | |
dc.contributor.author | Brandt, Roland | |
dc.date.accessioned | 2024-01-04T14:08:54Z | - |
dc.date.available | 2024-01-04T14:08:54Z | - |
dc.date.issued | 2002 | |
dc.identifier.uri | http://osnascholar.ub.uni-osnabrueck.de/handle/unios/73376 | - |
dc.description.abstract | Aggregation and increased phosphorylation of tau at selected sites ("hyperphosphorylation") are histopathological hallmarks of Alzheimer's disease (AD). However, it is not known whether the tau pathology has a primary role during neuronal degeneration. To determine the role of tau hyperphosphorylation in AD, pseudohyperphosphorylated tau (PHP-tau) that simulates disease-like permanent, high stoichiometric tau phosphorylation and mimics structural and functional aspects of hyperphosphorylated tau was expressed in neural cells. In differentiated PC12 cells, PHP-tau exhibited reduced microtubule interaction and failed to stabilize the microtubule network compared with exogenously expressed wild-type tau (wt-tau). During longer culture, PHP-tau exerted a cytotoxic effect, whereas wt-tau was neutral. PHP-tau-mediated cytotoxicity was associated with an induction of apoptotic cell death as characterized by chromatin condensation, DNA fragmentation, and caspase-3 activation in the absence of detectable protein aggregates. Furthermore, PHP-tau expression specifically sensitized the cells for other apoptotic stimuli (colchicine and staurosporine). Herpes simplex virus-mediated overexpression of PHP-tau induced degeneration associated with an induction of apoptotic mechanisms also in terminally differentiated human CNS model neurons. Partially pseudophosphorylated constructs caused an intermediate toxicity. The data provide evidence for a neurotoxic "gain of function" of soluble tau during AD as a result of structural changes that are induced by a cumulative, high stoichiometric tau phosphorylation. PHP-tau-expressing cells and organisms could provide a useful system to identify mechanisms that contribute to tau-mediated toxicity. | |
dc.language.iso | en | |
dc.relation.ispartof | The Journal of neuroscience : the official journal of the Society for Neuroscience | |
dc.source | PubMed | |
dc.title | Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease | |
dc.type | journal article | |
dc.identifier.doi | 10.1523/JNEUROSCI.22-22-09733.2002 | |
dc.identifier.pmid | 12427828 | |
dc.identifier.url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757822 | |
dc.contributor.affiliation | Department of Neurobiology, University of Osnabrück, 49076 Osnabrück, Germany. | |
dc.description.volume | 22 | |
dc.description.issue | 22 | |
dc.description.startpage | 9733 | |
dc.description.endpage | 9741 | |
local.import.remains | U3 : Journal Article Research Support, Non-U.S. Gov't Journal Article Research Support, Non-U.S. Gov't | |
local.import.sourcefile | ./Brandt_Roland_sk_Citavi_20231215.ris | |
crisitem.author.orcid | 0000-0003-0101-1257 | - |
crisitem.author.netid | BrRo587 | - |
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geprüft am 20.05.2024