Rapamycin Affects the Hippocampal SNARE Complex to Alleviate Cognitive Dysfunction Induced by Surgery in Aged Rats.

Delayed neurocognitive recovery (dNCR) is a common complication that occurs post-surgery, especially in elderly individuals. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex plays an essential role in various membrane fusion events, such as synaptic vesicle exocytosis and autophagosome-lysosome fusion. Although SNARE complex dysfunction has been observed in several neurodegenerative disorders, the causal link between SNARE-mediated membrane fusion and dNCR remains unclear. We previously demonstrated that surgical stimuli caused cognitive impairment in aged rats by inducing α-synuclein accumulation, inhibiting autophagy, and disrupting neurotransmitter release in hippocampal synaptosomes. Here, we evaluated the effects of propofol anesthesia plus surgery on learning and memory and investigated levels of SNARE proteins and chaperones in hippocampal synaptosomes. Aged rats that received propofol anesthesia and surgery exhibited learning and memory impairments in a Morris water maze test and decreased levels of synaptosome-associated protein 25, synaptobrevin/vesicle-associated membrane protein 2, and syntaxin 1. Levels of SNARE chaperones, including mammalian uncoordinated-18, complexins 1 and 2, cysteine string protein-α, and N-ethylmaleimide-sensitive factor, were all significantly decreased following anesthesia with surgical stress. However, the synaptic vesicle marker synaptophysin was unaffected. The autophagy-enhancer rapamycin attenuated structural and functional disturbances of the SNARE complex and ameliorated disrupted neurotransmitter release. Our results indicate that perturbations of SNARE proteins in hippocampal synaptosomes may underlie the occurrence of dNCR. Moreover, the protective effect of rapamycin may partially occur through recovery of SNARE structural and functional abnormalities. Our findings provide insight into the molecular mechanisms underlying dNCR.

Low-Intensity Pulsed Ultrasound Attenuates Postoperative Neurocognitive Impairment and Salvages Hippocampal Synaptogenesis in Aged Mice.

Postoperative neurocognitive impairment is an urgent problem with global aging accelerating. The prevention and treatment of postoperative neurocognitive impairment have been widely investigated but lack effective strategies. Low-intensity pulsed ultrasound (LIPUS), a non-invasive tool, has shown an effect on neuroprotection, but whether it could attenuate the postoperative neurocognitive impairment and the underlying mechanisms remains unknown. An experimental setup for LIPUS stimulation of the hippocampus was well established. A laparotomy model in aged mice was applied, and a Morris water maze was used to assess cognitive function. RT-qPCR and western blotting were used to detect levels of Piezo1, synapse-associated proteins in the hippocampus, respectively. Immunofluorescent staining was also used to determine the neural activation and Piezo1 expression. The results showed that LIPUS increased synapse-related proteins of the hippocampus and attenuated cognitive impairment in aged mice. Meanwhile, LIPUS suppressed the overexpression of Piezo1 in the hippocampus. We further found that LIPUS promoted Calpain1 activity and increased extracellular regulated protein kinases (Erk) phosphorylation. Our results suggested that LIPUS could improve cognitive impairment and increase hippocampal synaptogenesis through the Piezo1-mediated Calpain1/ Erk pathway. LIPUS could be used as an effective physical intervention to alleviate postoperative cognitive dysfunction in the aged population.

Preoperative intestinal microbiome and metabolome in elderly patients with delayed neurocognitive recovery.

BACKGROUND: Delayed neurocognitive recovery (dNCR) is a common complication of the central nervous system in elderly patients. Currently, it is not clear whether the occurrence of dNCR is associated with the intestinal microbiota and its related metabolites. This study investigated the preoperative intestinal microflora and faecal metabolites of dNCR patients. METHODS: Twenty-two elderly urological patients were divided into a dNCR group (D group) and a non-dNCR group (ND group) according to the postoperative Mini-Mental State Examination (MMSE) score on the first and third day after surgery. A postoperative MMSE score ≤ 2 points compared with the preoperative score was considered evidence of dNCR. We used a comprehensive method that combined 16S rRNA gene sequencing and untargeted metabolomics to study the preoperative intestinal microflora and faecal metabolites of the two groups, and conducted correlation analysis between them. RESULTS: Compared with the D group, the microbial community in the ND group was more abundant. At the family level, the ND group was significantly enriched in Lachnospiraceae, Peptostreptococcaceae and Muribaculaceae. At the genus level, the faecal microbiota of the ND group was differentially enriched in Agathobacter, Dorea, Fusicatenibacter, Coprococcus_2 and Romboutsia while that of the D group was differentially enriched in Anaerofilum. Untargeted metabolomics revealed significant differences in eight different metabolites between the two groups, including ribose, ethanol, leucine, maltose, pentadecanoic acid, malonic acid 1,3,4-dihydroxybenzoic acid and 3-hydroxypalmitic acid. In addition, differential metabolites were associated with the abundance of specific bacteria. CONCLUSIONS: The occurrence of dNCR may be associated with the intestinal flora and its related metabolite composition of patients before surgery.