Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease
Autor(en): | Fath, T Eidenmuller, J Brandt, R |
Stichwörter: | Alzheimer's disease; APOPTOSIS; BETA-PEPTIDE; HIPPOCAMPAL-NEURONS; human model neurons; hyperphosphorylation; MICROTUBULE-BINDING; MUTANT-TAU; NEUROFIBRILLARY TANGLES; Neurosciences; Neurosciences & Neurology; PAIRED HELICAL FILAMENTS; PC12 CELLS; PHOSPHORYLATION; PROTEIN-TAU; tau | Erscheinungsdatum: | 2002 | Herausgeber: | SOC NEUROSCIENCE | Journal: | JOURNAL OF NEUROSCIENCE | Volumen: | 22 | Ausgabe: | 22 | Startseite: | 9733 | Seitenende: | 9741 | Zusammenfassung: | 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. |
ISSN: | 02706474 |
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