Exosomal Let-7b-5p reduces postoperative cognitive dysfunction by enhancing autophagy through the GPR137/AMPK/mTOR signaling pathway

Postoperative cognitive dysfunction (POCD) is one of the most common complications in elderly patients undergoing anesthesia and surgery. This condition mainly involves problems with memory and cognitive deterioration. Nevertheless, it should be noted that although POCD is a clinically significant phenomenon, the molecular mechanisms of this disorder are not yet well known.

A POCD model was developed in 15 months old C57BL/6J male mice using laparotomy under sevoflurane anesthesia. Behavioral tests were performed for evaluation of cognition. Inhibition or upregulation of let-7b-5p and GPR137 was done by their inhibitors or mimics or adeno-associated virus (AAV) vectors.

Autophagy, neuroinflammation, and AMPK/mTOR signaling pathway were evaluated by immunofluorescence and Western blotting along with quantitative PCR (qPCR). Surgical interventions resulted in noticeable cognitive deficits, neuronal death, and neuroinflammation in the hippocampal region, which was along with the reduction of Let-7b-5p and increase in GPR137. Treatment with exosomes enriched with Let-7b-5p substantially improved cognitive impairments and prevented neuronal cell death.

Let-7b-5p inhibited GPR137 through direct binding, resulting in the reduction in GPR137 levels. Reduced GPR137 stimulated AMPK pathway while inhibiting the activation of mTOR, promoting autophagy process. Exosomal Let-7b-5p enhances neuronal autophagy through the AMPK/mTOR axis by targeting GPR137, thereby exerting neuroprotective effects.

These findings suggest that Let-7b-5p may represent a potential therapeutic target for POCD. We thank all the authors involved in the study. The authors have reviewed and edited the output and take full responsibility for the content of this publication.

This research was funded by Scientific research project of Sichuan Provincial Preventive Medicine Association (No. Department of Anesthesiology, The Third People’s Hospital of Chengdu (The Affiliated Hospital of Southwest Jiaotong University), College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China Department of Anesthesiology, Mianyang Maternal and Child Health Hospital, Mianyang, Sichuan, China College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China The authors declare no competing interests. The animal study protocol was approved by the Ethics Committee of the Third People’s Hospital of Chengdu (The Affiliated Hospital of Southwest Jiaotong University) (No. 2024-S-334) and conducted following the approved guidelines.