title: Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease.
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.
authors.affiliation: Department of Neurobiology, University of Osnabrück, 49076 Osnabrück, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fath
authors.forename: Jochen
authors.initials: J
authors.lastname: Eidenmüller
authors.forename: Roland
authors.initials: R
authors.lastname: Brandt
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D018139:Simplexvirus / Q000235:genetics; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D016875:tau Proteins / Q000096:biosynthesis / Q000235:genetics / Q000633:toxicity*
chemical_list: D004791:Enzyme Inhibitors; D016875:tau Proteins; D020932:Nerve Growth Factor; D019311:Staurosporine; D003078:Colchicine