Ginsenoside 1 mitigates postoperative cognitive dysfunction by enhancing microglial Aβ clearance through the endo-lysosomal pathway

Background: Postoperative cognitive dysfunction (POCD) is a common complication in patients after surgery, especially in the elderly. The incidence of POCD not only impaired learning and memory, but also increased morbidity and mortality in patients. However, the exploration of therapeutic agents is limited. Ginsenoside 1 (Rg1) is one of the main compounds of ginseng, which exhibits bioactive and neuroprotective efficiency. In the present study, we aimed to investigate the effects of Rg1 on POCD.

Methods: The POCD model was established by performing aseptic laparotomy surgery under anesthesia in 18-month mice. The cognition and anxiety of mice were assessed with MWM, OFT, and NOR tests. An in vitro model was performed on BV2 microglial cells. RNA Sequencing, Western blotting, electrophysiology, Golgi staining, engulfment, and immunofluorescence analysis were performed.

Results: Our results showed that Rg1 effectively alleviated the cognitive dysfuncion and anxiety of POCD mice. Transcriptomic Sequencing data in microglia indicated that Rg1 mainly affects endosomes and lysosomes. By upregulating Rab7 and TFEB expression, Rg1 promoted microglial engulfment of Aβ through the endo-lysosomal pathway. Additionally, Rg1 reduced inflammatory levels, increased synaptic plasticity, and mitigated neuronal damage caused by Aβ. Moreover, the effects of Rg1 on TFEB depended on MEK/ERK signaling, while activation of MEK reversed Rg1's protective effects.

Conclusions: In conclusion, our study demonstrates that Rg1 can effectively ameliorate cognitive and synaptic deficit by enhancing microglial Aβ clearance through the endo-lysosomal pathway in aged POCD mice, which provides a potential strategy for the prevention of POCD.

Aβ; Endo-lysosomal; Microglia; POCD; Rg1; TFEB.