Research Paper Volume 12, Issue 8 pp 7262—7281

Autophagy prevents hippocampal α-synuclein oligomerization and early cognitive dysfunction after anesthesia/surgery in aged rats

Ning Yang 1, *, , Zhengqian Li 1, *, , Dengyang Han 1, , Xinning Mi 1, , Miao Tian 2, , Taotao Liu 1, , Yue Li 1, , Jindan He 1, , Chongshen Kuang 1, , Yiyun Cao 3, , Lunxu Li 4, , Cheng Ni 1, , John Q. Wang 5, , Xiangyang Guo 1, ,

  • 1 Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China
  • 2 Chinese Traditional and Herbal Drugs Editorial Office, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
  • 3 Department of Anesthesiology, Shanghai Sixth People’s Hospital East Affiliated with Shanghai University of Medicine and Health Sciences, Shanghai 200233, China
  • 4 Department of Anesthesiology, Peking University International Hospital, Beijing 102200, China
  • 5 Department of Anesthesiology, University of Missouri Kansas City, School of Medicine, Kansas, MO 64110, USA
* Equal contribution

received: August 23, 2019 ; accepted: March 29, 2020 ; published: April 26, 2020 ;

https://doi.org/10.18632/aging.103074
How to Cite

Copyright © 2020 Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Stress-induced α-synuclein aggregation, especially the most toxic species (oligomers), may precede synaptic and cognitive dysfunction. Under pathological conditions, α-synuclein is degraded primarily through the autophagic/lysosomal pathway. We assessed the involvement of autophagy in α-synuclein aggregation and cognitive impairment following general anesthesia and surgical stress. Autophagy was found to be suppressed in the aged rat hippocampus after either 4-h propofol anesthesia alone or 2-h propofol anesthesia during a laparotomy surgery. This inhibition of autophagy was accompanied by profound α-synuclein oligomer aggregation and neurotransmitter imbalances in the hippocampus, along with hippocampus-dependent cognitive deficits. These events were not observed 18 weeks after propofol exposure with or without surgical stress. The pharmacological induction of autophagy using rapamycin markedly suppressed α-synuclein oligomerization, restored neurotransmitter equilibrium, and improved cognitive behavior after prolonged anesthesia or anesthesia combined with surgery. Thus, both prolonged propofol anesthesia alone and propofol anesthesia during surgery impaired autophagy, which may have induced abnormal hippocampal α-synuclein aggregation and neurobehavioral deficits in aged rats. These findings suggest that the activation of autophagy and the clearance of pathological α-synuclein oligomers may be novel strategies to ameliorate the common occurrence of postoperative cognitive dysfunction.

Abbreviations

POCD: postoperative cognitive dysfunction; MWM: Morris water maze; FCT: fear conditioning test; LC3: microtubule-associated protein 1 light chain 3; SDS: sodium dodecyl sulphate; CA1: cornu ammonis 1; DG: dentate gyrus; CON: the control group; PRO2: the 2-h propofol group; PRO4: the 4-h propofol group; PRO2S: the 2-h propofol anesthesia + surgery group; CON + RAP: the control + rapamycin group; PRO4 + RAP: the 4-h propofol anesthesia + rapamycin group; PRO2S + RAP: the 2-h propofol anesthesia + surgery + rapamycin group.