Affiliations: [a] Institute of Neuroimmunology, Slovak Academy of Sciences, AD Centre, Bratislava, Slovak Republic | [b] Axon-Neuroscience GmbH, Vienna, Austria
Correspondence:
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Correspondence to: Michal Novak, MVD, PhD, Dubravska cesta 9, 845 10 Bratislava, Slovak Republic. Tel.: +421 2 5477 8100; Fax: +421 2 5477 8100; Email: [email protected].
Abstract: Neurofibrillary degeneration and neuronal loss represent key pathological hallmarks of Alzheimer's disease (AD). It has been demonstrated that the decrease of total neuronal numbers correlates with the presence of neurofibrillary degeneration in AD brain. In order to unravel the mechanism leading to the cell death in AD, we developed a stably transfected human neuroblastoma cellular model with doxycycline-regulatable expression of AD truncated tau protein (AT tau, 151-391 4R). Cells expressing the longest tau isoform (Tau 40) were used as a control. We found that more than 80% of the total amount of AT tau and Tau 40 were phosphorylated. Strikingly, both AT tau and Tau 40 reduced the metabolic activity of the cells in a time-dependent manner (p < 0.0001) suggesting that tau overexpression slows down cell proliferation. However, AT tau showed significantly higher toxicity than Tau 40 (p < 0.0001), which indicates that truncation leads to a toxic gain of function. The analysis of the type of the cell death revealed the characteristic features of apoptosis such as cell shrinkage, nuclear, and DNA fragmentation. However, we did not find either the activation of executive caspase (caspase-3) or the caspase cleavage products (PARP and fodrin). These results show that posttranslationally modified truncated tau protein induces caspase-3-independent apoptosis-like programmed cell death, a phenomenon we term tauoptosis.
Keywords: Alzheimer's disease, apoptosis, cell death, cell model, truncated tau protein
