1. Tau Contributes to Sevoflurane-induced Neurocognitive Impairment in Neonatal Mice
- Author
-
Yongyan Yang, Yiying Zhang, Yonghao Yu, Myriam Boukhali, Hong Tan, Wilhelm Haas, Ling Liu, Mengzhu Li, Yuanlin Dong, Yang Yu, Fuzhou Hua, Guang Yang, Zhongcong Xie, and Ashok Khatri
- Subjects
Male ,medicine.medical_specialty ,Arbitrary unit ,Morris water navigation task ,tau Proteins ,Article ,Sevoflurane ,Mice ,03 medical and health sciences ,0302 clinical medicine ,030202 anesthesiology ,Internal medicine ,medicine ,Animals ,Hippocampus (mythology) ,Cognitive Dysfunction ,business.industry ,Vitamin K2 ,Age Factors ,Brain ,Metabolism ,Disease Models, Animal ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Endocrinology ,Animals, Newborn ,Cerebral cortex ,Anesthetics, Inhalation ,Phosphorylation ,business ,030217 neurology & neurosurgery ,medicine.drug - 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 What This Article Tells Us That Is New
- Published
- 2020