Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease
Autor(en): | Fath, Thomas Eidenmüller, Jochen Brandt, Roland |
Affiliationen: | Department of Neurobiology, University of Osnabrück, 49076 Osnabrück, Germany. | Erscheinungsdatum: | 2002 | Journal: | The Journal of neuroscience : the official journal of the Society for 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. |
DOI: | 10.1523/JNEUROSCI.22-22-09733.2002 | Externe URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757822 |
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geprüft am 10.05.2024