Perioperative Medicine  |   September 2020
Tau Contributes to Sevoflurane-induced Neurocognitive Impairment in Neonatal Mice
Author Notes
  • From the Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, China (Yang Yu, Y. Yang, Yonghao Yu); the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts (Yang Yu, Y. Yang, H.T., F.H., L.L., M.L., Y.D., Y.Z., Z.X.); the Department of Anesthesia, Xinhua Hospital of Shanghai Jiaotong University, Shanghai, China (H.T.); the Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (M.B., W.H.); the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (A.K.); the Department of Anesthesia, Second Affiliated Hospital of Nanchang University, Nanchang, China (F.H.); Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China (L.L.), Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China (M.L.); and the Department of Anesthesiology, Columbia University Medical Center, New York, New York (G.Y.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Yang Yu and Y. Yang contributed equally to this work.
    Yang Yu and Y. Yang contributed equally to this work.×
  • Submitted for publication April 20, 2019. Accepted for publication June 9, 2020. Published online first on July 14, 2020.
    Submitted for publication April 20, 2019. Accepted for publication June 9, 2020. Published online first on July 14, 2020.×
  • Address correspondence to Dr. Xie: Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 4310, Charlestown, Massachusetts 02129-2060. zxie@mgh.harvard.edu. Anesthesiology’s articles are made freely accessible to all readers on www.anesthesiology.org, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Basic Science / Central and Peripheral Nervous Systems / Pediatric Anesthesia / Pharmacology
Perioperative Medicine   |   September 2020
Tau Contributes to Sevoflurane-induced Neurocognitive Impairment in Neonatal Mice
Anesthesiology 9 2020, Vol.133, 595-610. doi:https://doi.org/10.1097/ALN.0000000000003452
Anesthesiology 9 2020, Vol.133, 595-610. doi:https://doi.org/10.1097/ALN.0000000000003452
Abstract

Background: Sevoflurane anesthesia induces Tau phosphorylation and cognitive impairment in neonatal but not in adult mice. This study tested the hypothesis that differences in brain Tau amounts and in the activity of mitochondria–adenosine triphosphate (ATP)–Nuak1–Tau cascade between the neonatal and adult mice contribute to the age-dependent effects of sevoflurane on cognitive function.

Methods: 6- and 60-day-old mice of both sexes received anesthesia with 3% sevoflurane for 2 h daily for 3 days. Biochemical methods were used to measure amounts of Tau, phosphorylated Tau, Nuak1, ATP concentrations, and mitochondrial metabolism in the cerebral cortex and hippocampus. The Morris water maze test was used to evaluate cognitive function in the neonatal and adult mice.

Results: Under baseline conditions and compared with 60-day-old mice, 6-day-old mice had higher amounts of Tau (2.6 ± 0.4 [arbitrary units, mean ± SD] vs. 1.3 ± 0.2; P < 0.001), Tau oligomer (0.3 ± 0.1 vs. 0.1 ± 0.1; P = 0.008), and Nuak1 (0.9 ± 0.3 vs. 0.3 ± 0.1; P = 0.025) but lesser amounts of ATP (0.8 ± 0.1 vs. 1.5 ± 0.1; P < 0.001) and mitochondrial metabolism (74.8 ± 14.1 [pmol/min] vs. 169.6 ± 15.3; P < 0.001) in the cerebral cortex. Compared with baseline conditions, sevoflurane anesthesia induced Tau phosphorylation at its serine 202/threonine 205 residues (1.1 ± 0.4 vs. 0.2 ± 0.1; P < 0.001) in the 6-day-old mice but not in the 60-day-old mice (0.05 ± 0.04 vs. 0.03 ± 0.01; P = 0.186). The sevoflurane-induced Tau phosphorylation and cognitive impairment in the neonatal mice were both attenuated by the inhibition of Nuak1 and the treatment of vitamin K2.

Conclusions: Higher brain Tau concentrations and lower brain mitochondrial metabolism in neonatal compared with adult mice contribute to developmental stage–dependent cognitive dysfunction after sevoflurane anesthesia.

Editor’s Perspective:

What We Already Know about This Topic:

  • Pathologic aggregation of the neuronal microtubule-associated protein Tau is a hallmark of Alzheimer’s disease

  • Sevoflurane anesthesia induces Tau phosphorylation and cognitive impairment in neonatal but not in adult mice, but the molecular mechanisms underlying these age-dependent effects have not been previously reported

What This Article Tells Us That Is New:

  • Neonatal mice have higher brain Tau levels and higher brain concentrations of Nuak1, an enzyme that phosphorylates Tau, when compared with adult counterparts

  • Neonatal mice have decreased mitochondrial activity and lower brain ATP concentrations when compared with adult counterparts

  • Pharmacologic inhibition of Tau phosphorylation or enhancement of mitochondrial function in neonatal mice protects against sevoflurane anesthesia–induced cognitive deficits

  • These observations suggest that developmental stage–dependent differences in mitochondrial activity and Tau phosphorylation can render neonatal mice more vulnerable to the development of Tauopathy and cognitive impairment after sevoflurane anesthesia