DC Field | Value | Language |
dc.contributor.author | Fath, T | |
dc.contributor.author | Eidenmuller, J | |
dc.contributor.author | Brandt, R | |
dc.date.accessioned | 2021-12-23T16:11:59Z | - |
dc.date.available | 2021-12-23T16:11:59Z | - |
dc.date.issued | 2002 | |
dc.identifier.issn | 02706474 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/9989 | - |
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.publisher | SOC NEUROSCIENCE | |
dc.relation.ispartof | JOURNAL OF NEUROSCIENCE | |
dc.subject | Alzheimer's disease | |
dc.subject | APOPTOSIS | |
dc.subject | BETA-PEPTIDE | |
dc.subject | HIPPOCAMPAL-NEURONS | |
dc.subject | human model neurons | |
dc.subject | hyperphosphorylation | |
dc.subject | MICROTUBULE-BINDING | |
dc.subject | MUTANT-TAU | |
dc.subject | NEUROFIBRILLARY TANGLES | |
dc.subject | Neurosciences | |
dc.subject | Neurosciences & Neurology | |
dc.subject | PAIRED HELICAL FILAMENTS | |
dc.subject | PC12 CELLS | |
dc.subject | PHOSPHORYLATION | |
dc.subject | PROTEIN-TAU | |
dc.subject | tau | |
dc.title | Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease | |
dc.type | journal article | |
dc.identifier.isi | ISI:000179147000010 | |
dc.description.volume | 22 | |
dc.description.issue | 22 | |
dc.description.startpage | 9733 | |
dc.description.endpage | 9741 | |
dc.contributor.orcid | 0000-0003-0101-1257 | |
dc.contributor.orcid | 0000-0002-6877-7567 | |
dc.publisher.place | 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA | |
dcterms.isPartOf.abbreviation | J. Neurosci. | |
crisitem.author.orcid | 0000-0003-0101-1257 | - |
crisitem.author.netid | BrRo587 | - |