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A Synergic Role of Caspase-6 and Caspase-3 in Tau Truncation at D421 Induced by H2O2

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Abstract

Tau truncation is widely detected in Alzheimer’s disease brain. Caspases activation is suggested to play a significant role in tau truncation at Aspartate 421 (D421) according to their ability to cleave recombinant tau in vitro. Ample evidence has shown that caspase-6 is involved in cognitive impairment and expressed in AD brain. Reactive oxygen species (ROS) can lead to caspase-6 activation and correlate with AD. Here, we transfected human embryonic kidney 293 (HEK 293) cells with Tau 441 plasmid and investigated the role of caspase-6 and caspase-3 in ROS-mediated tau truncation. Our data demonstrated that H2O2 induced oxidative stress and increased tau truncation. Caspase-6 and caspase-3 activity also increased in a dose-dependent manner in HEK 293/Tau cells during H2O2 insult. When cells were treated with an ROS inhibitor N-acetyl-l-cysteine, tau truncation was significantly suppressed. Compared with H2O2 (100 μM)/non-inhibitor group or single-inhibitor groups (z-VEID-fmk, caspase-6 inhibitor or z-DEVD-fmk, and caspase-3 inhibitor), tau truncation induced by H2O2 was effectively reduced in the combinative inhibitors group. Similar results were shown when cells were transfected with specific caspase-3 and caspase-6 siRNA. Inhibition of caspase-6 led to decline of caspase-3 activation. Taken together, our results suggest that the combination of caspase-6 and caspase-3 aggravates tau truncation at D421 induced by H2O2. Caspase-6 may play an important part in activating caspase-3. Further investigation of how the synergic role of caspase-6 and caspase-3 affects tau truncation may provide new visions for potential AD therapies.

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Acknowledgments

We are grateful to Dr. Jianzhi Wang (Huazhong University of Science and Technology, Wuhan, China) for the plasmid of longest human tau. This work was supported by grants from the National Natural Science Foundation of China (30970685, 81270432).

Conflict of interest

No conflicts of interest were declared.

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Authors and Affiliations

  1. School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China

    Hong Zhao, Wenjuan Zhao, Kenghoe Lok, Zejian Wang & Ming Yin

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  1. Hong Zhao
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  2. Wenjuan Zhao
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  3. Kenghoe Lok
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  4. Zejian Wang
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  5. Ming Yin
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Correspondence to Zejian Wang or Ming Yin.

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Zhao, H., Zhao, W., Lok, K. et al. A Synergic Role of Caspase-6 and Caspase-3 in Tau Truncation at D421 Induced by H2O2 . Cell Mol Neurobiol 34, 369–378 (2014). https://doi.org/10.1007/s10571-013-0021-x

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