Anesthetic Isoflurane Increases Phosphorylated Tau Levels Mediated by Caspase Activation and Aβ Generation

Yuanlin Dong,Zhongcong Xie,Xu Wu,Zhipeng Xu,Yiying Zhang,Jialin Charles Zheng

doi:10.1371/journal.pone.0039386

Yuanlin Dong, Zhongcong Xie + Show 4 more

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https://doi.org/10.1371/journal.pone.0039386

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Abstract

Anesthetic isoflurane has been shown to promote Alzheimer’s disease (AD) neuropathogenesis by inducing caspase activation and accumulation of β-amyloid (Aβ). Phosphorylation of tau protein is another important feature of AD neuropathogenesis. However, the effects of isoflurane on phosphorylated tau levels remain largely to be determined. We therefore set out to determine whether isoflurane can increase phosphorylated tau levels. 5 to 8 month-old wild-type and AD transgenic mice [B6.Cg-Tg (APPswe, PSEN1dE9)85Dbo/J] were treated with 1.4% isoflurane for two hours. The mice brain tissues were harvested at six, 12 and 24 hours after the anesthesia. For the in vitro studies, primary neurons from wild-type and the AD transgenic mice were exposed to 2% isoflurane for six hours, and were harvested at the end of anesthesia. The harvested brain tissues and neurons were subjected to Western blot analysis by which the levels of phosphorylated tau protein at Serine 262 (Tau-PS262) were determined. Here we show that the isoflurane anesthesia increased Tau-PS262 levels in brain tissues and primary neurons from the wild-type and AD transgenic mice. Moreover, the isoflurane anesthesia may induce a greater increase in Tau-PS262 levels in primary neurons and brain tissues from the AD transgenic mice. Finally, caspase activation inhibitor Z-VAD and Aβ generation inhibitor L-685,458 attenuated the isoflurane-induced increases in Tau-PS262 levels. In conclusion, clinically relevant isoflurane anesthesia increases phosphorylated tau levels, which may result from the isoflurane-induced caspase activation and Aβ generation. These findings will promote more studies to determine the effects of anesthetics on tau phosphorylation.

Highlights

Alzheimer’s disease (AD) is an insidious and progressive neurodegenerative disorder
The isoflurane anesthesia increased the levels of Tau-PS262 in mice brain tissues at 24 hours after the anesthesia (Figure 1e and Figure 1f): 100% versus 177%, *P = 0.019
We used tau knockout mice brain tissues as negative controls in our studies and found that isoflurane anesthesia led to a more visible band in the Western blot analysis as compared to control condition in WT mice brain tissues, whereas tau knockout mice brain tissues did not show such band (Figure 1h). These data indicated that the bands (55 kDa) observed following the isoflurane anesthesia in current experiments were phosphorylated tau. These results suggest that isoflurane anesthesia may induce tau phosphorylation in WT mice brain tissues, as evidenced that the isoflurane anesthesia increased the levels of phosphorylated tau, but not total tau

Summary

Introduction

Alzheimer’s disease (AD) is an insidious and progressive neurodegenerative disorder. Currently, there is no cure for AD. If the onset of AD could be delayed by just one year in those who develop this mind-destroying ailment, the number of worldwide AD cases would be reduced by 12 million by 2050 (2nd Alzheimer’s Association International Conference on Prevention of Dementia in Washington, D.C., June, 2007). It is important to identify any environmental factors which may promote AD development and AD neuropathogenesis. An estimated 200 million patients worldwide undergo anesthesia and surgery each year. Several recent studies reported that general anesthesia could be a risk factor for the development of AD [3,4]. More population and basic studies defining the role of anesthesia in AD development and AD neuropathogenesis are needed [9]

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