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

ABSTRACT: Stress-induced ?-synuclein aggregation, especially the most toxic species (oligomers), may precede synaptic and cognitive dysfunction. Under pathological conditions, ?-synuclein is degraded primarily through the autophagic/lysosomal pathway. We assessed the involvement of autophagy in ?-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 ?-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 ?-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 ?-synuclein aggregation and neurobehavioral deficits in aged rats. These findings suggest that the activation of autophagy and the clearance of pathological ?-synuclein oligomers may be novel strategies to ameliorate the common occurrence of postoperative cognitive dysfunction.

SUBMITTER: Yang N

PROVIDER: S-EPMC7202547 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Yang Ning N Li Zhengqian Z Han Dengyang D Mi Xinning X Tian Miao M Liu Taotao T Li Yue Y He Jindan J Kuang Chongshen C Cao Yiyun Y Li Lunxu L Ni Cheng C Wang John Q JQ Guo Xiangyang X

Aging 20200426 8

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 ...[more]

PMID: 32335546

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Project description:Cognitive dysfunction is a salient feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). The onset of dementia reflects the spread of Lewy pathology throughout forebrain structures. The mere presence of Lewy pathology, however, provides limited indication of cognitive status. Thus, it remains unclear whether Lewy pathology is the de facto substrate driving cognitive dysfunction in PD and DLB. Through application of α-synuclein fibrils in vivo , we sought to examine the influence of pathologic inclusions on cognition. Following stereotactic injection of α-synuclein fibrils within the mouse forebrain, we measured the burden of α-synuclein pathology at 1-, 3-, and 6-months post-injection within subregions of the hippocampus and cortex. Under this paradigm, the hippocampal CA2/3 subfield was especially susceptible to α- synuclein pathology. Strikingly, we observed a drastic reduction of pathology in the CA2/3 subfield across time-points, consistent with the consolidation of α-synuclein pathology into dense somatic inclusions followed by neurodegeneration. Silver-positive degenerating neurites were observed prior to neuronal loss, suggesting that this might be an early feature of fibril-induced neurotoxicity and a precursor to neurodegeneration. Critically, mice injected with α-synuclein fibrils developed progressive deficits in spatial learning and memory. These findings support that the formation of α-synuclein inclusions in the mouse forebrain precipitate neurodegenerative changes that recapitulate features of Lewy-related cognitive dysfunction.HighlightsMice injected with α-synuclein fibrils develop hippocampal and cortical α- synuclein pathology with a dynamic regional burden at 1-, 3-, and 6-months post-injection.Silver-positive neuronal processes are an early and enduring degenerative feature of the fibril model, while extensive neurodegeneration of the hippocampal CA2/3 subfield is detected at 6-months post-injection.Mice exhibit progressive hippocampal-dependent spatial learning and memory deficits.Forebrain injection of α-synuclein fibrils may be used to model aspects of Lewy-related cognitive dysfunction.

Dataset Information

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

Publications

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

Similar Datasets

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