Previous studies have shown that exposure to inhaled anesthetics can cause cognitive dysfunction, suggesting that general anesthesia might be a risk factor for the development of Alzheimer disease. However, the underlying mechanisms remain to be elucidated. In the present study, we tested our hypothesis that enhanced tau protein phosphorylation in hippocampus contributes to isoflurane-induced cognitive dysfunction in a mouse model of Alzheimer disease.
Fifty-four male wild-type (WT) mice (12 months old) and 54 male amyloid precursor protein 695 (APP695) mice (12 months old) were either anesthetized for 4 hours with 1.0 minimum alveolar concentration isoflurane or sham-anesthetized (control). Learning and memory behaviors were measured using the Morris Water Maze test for mice. Phosphorylation of hippocampal tau protein at Ser262 site was analyzed with quantitative Western blotting.
In the Morris Water Maze test, both WT and transgenic APP695 mice showed decreased latency times during a 4-day training period. Isoflurane exposure significantly increased the latency times on days 2 and 3 in WT mice as well as on days 3 and 4 in APP695 mice (WT: P = 0.005 for day 2 and P = 0.002 for day 3; APP695: P = 0.001 for day 3 and P < 0.0001 for day 4) and reduced platform quadrant times (WT: P < 0.0001; APP695: P < 0.0001) in both types of mice. Compared with WT mice, transgenic APP695 mice displayed worse learning and memory behaviors after isoflurane exposure (P = 0.0005 for escape latency testing on day 4 training; P = 0.009 for platform probe testing). Western blot analysis showed that the levels of phosphorylation of hippocampal tau protein at Ser262 site (tau[pS262]) in the transgenic APP695 mice were higher than those in WT mice (P < 0.0001) and that isoflurane exposure time dependently enhanced the hippocampal tau[pS262] levels in both types of mice, but this effect was much more significant in the transgenic APP695 mice (P < 0.0001). Our data also showed that isoflurane exposure had no effect on the expression of total tau protein in the hippocampi of all mice (P ≥ 0.54).
Isoflurane may induce cognitive dysfunction by enhancing phosphorylation of hippocampal tau protein at Ser262 site, and this effect is more significant in transgenic APP695 mice.
Published ahead of print June 23, 2014.Supplemental Digital Content is available in the text.
From the *College of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, China; †Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; ‡College of Basic Medicine, Xinxiang Medical University, Xinxiang, Henan, China; §Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, Texas.
Accepted for publication March 31, 2014.
Published ahead of print June 23, 2014.
Funding: This work is made possible by the grant from National Natural Science Fund of China 30940025 to Dr. Xing and National Institutes of Health grant R01DE022880 to Dr. Tao.
The authors declare no conflicts of interest.
Drs. Changsheng Li and Sufang Liu contributed equally to this manuscript.
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Address correspondence and reprint requests to Feng Tao, MD, PhD, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD 21205. Address email to firstname.lastname@example.org.