Autophagy prevents hippocampal α-synuclein oligomerization and early cognitive dysfunction after anesthesia/surgery in aged rats
Open Access
- 26 April 2020
- journal article
- research article
- Published by Impact Journals, LLC in Aging
- Vol. 12 (8), 7262-7281
- https://doi.org/10.18632/aging.103074
Abstract
Stress-induced alpha-synuclein aggregation, especially the most toxic species (oligomers), may precede synaptic and cognitive dysfunction. Under pathological conditions, alpha-synuclein is degraded primarily through the autophagic/lysosomal pathway. We assessed the involvement of autophagy in alpha-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 alpha-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 alpha-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 alpha-synuclein aggregation and neurobehavioral deficits in aged rats. These findings suggest that the activation of autophagy and the clearance of pathological alpha-synuclein oligomers may be novel strategies to ameliorate the common occurrence of postoperative cognitive dysfunction.Keywords
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