Hyperphosphorylated truncated protein tau induces caspase-3 independent apoptosis-like pathway in the Alzheimer's disease cellular model.
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.
Institute of Neuroimmunology, Slovak Academy of Sciences, AD Centre, Bratislava, Slovak Republic Axon-Neuroscience GmbH, Vienna, Austria.
Monika
M
Zilkova
Norbert
N
Zilka
Andrej
A
Kovac
Branislav
B
Kovacech
Rostislav
R
Skrabana
Michaela
M
Skrabanova
Michal
M
Novak
D000704:Analysis of Variance; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D002452:Cell Count; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014162:Transfection; D016875:tau Proteins / Q000235:genetics*; D013049:Spectrin
D002352:Carrier Proteins; D053148:Caspase 3; D008840:Microfilament Proteins; D016875:tau Proteins; D013049:Spectrin