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
Volumen: 22
Ausgabe: 22
Startseite: 9733
Seitenende: 9741
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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