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

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.

Inhibition of α-Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice

“…Moreover, α -syn can also impair the NMDA receptor-mediated LTP, an enhanced synaptic activity, which is widely accepted to be related to memory formation [ 46 ]. Meanwhile, our preliminary studies [ 15 , 16 ] and others [ 17 , 18 ] have demonstrated that α -syn may also be associated with surgery-induced cognitive impairment. However, the exact association between α -syn accumulation and the mechanism of dNCR is not fully understood.…”

“…Aggregation and propagation of misfolded α -syn in the brain are involved in the pathogenesis of neurodegenerative diseases, especially in Parkinson's disease cases [ 13 , 14 ]. In our earlier work, we demonstrated that anesthesia and surgery increased α -syn oligomerization and disturbed neurotransmitter homeostasis in the hippocampus of aged rats, while exosome α -syn release into the plasma of postoperative delirium (POD) patients with hip fractures was significantly higher compared with non-POD cases [ 15 , 16 ]. In addition, an earlier study from another laboratory found elevated total α -syn expression in the cortex after 12 h, with attention deficit after 24 h in mice following anesthesia plus surgery [ 17 ].…”

“…Fear Conditioning Test (FCT). The FCT was based on a previous study with minor modifications [16]. The test phase of the FCT includes a context test that reflects hippocampaldependent memory and a tone test that evaluates hippocampal-independent memory.…”

Update on the Mechanism and Treatment of Sevoflurane-Induced Postoperative Cognitive Dysfunction

“…α-Synuclein, a protein containing 140 amino acids, is primarily located at the presynaptic terminal and maintains neurotransmitter homeostasis. Anesthesia and surgery can inhibit hippocampal cell autophagy, increase α-synuclein oligomerization, cause a neurotransmitter imbalance, and induce POCD ( Yang N. et al, 2020 ). Since sevoflurane regulates the CNS and induces anesthesia by targeting different neurotransmitters and receptors on the synapses ( Qin et al, 2018 ; Yin et al, 2019 ), its effect on various neurotransmitters is another cause of sevoflurane-induced POCD.…”

Plasma Levels of Alpha and Gamma Synucleins in Autism Spectrum Disorder: An Indicator of Severity

“…Our findings indicated that there is an association between plasma levels of both α-synuclein and γ-synuclein and the severity of ASD compared to the control group as shown in Figure 3a–f. Previous studies also reported a correlation between both α-synuclein or γ-synuclein in memory, cognitive functions, and social communication [10, 27]. The association between intellectual disabilities and synaptic dysfunction in autistic children was found to be significant [28].…”