Interaction of Tau, IL-6 and mitochondria on synapse and cognition following sevoflurane anesthesia in young mice

Yuanlin Dong,Lining Huang Lining Huang,Zhongcong Xie,Xiaoming Xu,Yiying Zhang,Jie Zhang,Sulpicio G Soriano,Feng Liang

doi:10.1016/j.bbih.2020.100133

Abstract

Tau phosphorylation is associated with cognitive impairment in young mice. However, the underlying mechanism and targeted interventions remain mostly unknown. We set out to determine the potential interactions of Tau, interleukin 6 (IL-6) and mitochondria following treatment of anesthetic sevoflurane and to assess their influences on synapse number and cognition in young mice. Sevoflurane (3% for 2 h) was given to wild-type, Tau knockout, IL-6 knockout, and cyclophilin D (CypD) knockout mice on postnatal (P) day 6, 7 and 8. We measured amounts of phosphorylated Tau, IL-6, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP, postsynaptic density 95 (PSD-95), synaptophysin, N-cadherin, synapse number, and cognitive function in the mice, employing Western blot, electron microscope and Morris water maze among others. Here we showed that sevoflurane increased Tau phosphorylation and caused IL-6 elevation, mitochondrial dysfunction, synaptic loss and cognitive impairment in young wild-type, but not Tau knockout, mice. In young IL-6 knockout mice, sevoflurane increased Tau phosphorylation but did not cause mitochondrial dysfunction, synaptic loss or cognitive impairment. Finally, sevoflurane increased Tau phosphorylation and IL-6 amount, but did not induce synaptic loss and cognitive impairment, in young CypD knockout mice or WT mice pretreated with idebenone, an analog of co-enzyme Q10. In conclusion, sevoflurane increased Tau phosphorylation, which caused IL-6 elevation, leading to mitochondrial dysfunction in young mice. Such interactions caused synaptic loss and cognitive impairment in the mice. Idebenone mitigated sevoflurane-induced cognitive impairment in young mice. These studies would promote more research to study Tau in young mice.

Highlights

Our previous studies showed that anesthetic sevoflurane increased Tau phosphorylation in brain tissues of young mice and induced cognitive impairment in the young mice (Tao et al, 2014; Yu et al, 2020)
Employing sevoflurane as a clinically relevant tool, and WT, Tau KO, interleukin 6 (IL-6) KO, and cyclophilin D (CypD) KO young mice as the approaches, we demonstrated the interactions of Tau phosphorylation, IL-6 accumulation and mitochondrial dysfunction and the effects of such interactions on synapse number and cognitive impairment in young mice
The findings in the present studies suggest that Tau phosphorylation causes IL-6 elevation, which induces mitochondrial dysfunction, leading to synaptic loss and cognitive impairment in the young mice following sevoflurane anesthesia (Fig. 11)

Summary

Introduction

Our previous studies showed that anesthetic sevoflurane increased Tau phosphorylation in brain tissues of young mice and induced cognitive impairment in the young mice (Tao et al, 2014; Yu et al, 2020). Anesthetic sevoflurane increased Tau phosphorylation (Tao et al, 2014; Yu et al, 2020) and IL-6 amounts (Shen et al, 2013; Tao et al, 2014), caused mitochondrial dysfunction (Xu et al, 2017) and induced synaptic loss (Lu et al, 2017; Tao et al, 2014; Xu et al, 2017; Zhang et al, 2015) in brain tissues of young mice.

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Conclusion