Supporting data for "The role and mechanisms of neuroinflammation and glucose metabolism in the postoperative neurocognitive disorders"

PNDs has been observed for decades, which cause lower life quality, delayed recovery, and heavy medical burdens for both individuals and the community. Considering that an increasing population undergoes surgery, and over one-third are aged patients, this common surgical complication is becoming a great challenge for the society. Previous evidence has already showed that neuroinflammation and blood-brain barrier disruption are two critical pathological changes in PNDs, while their underlying mechanisms remain unclear, which make it difficult to find potential therapeutic targets. 
To illustrate the association between neuroinflammation and cognitive functions, this project firstly explored the feature of postoperative reactive astrocytes and searched for the key secreted factor that accelerates cognitive impairment by using RNA-sequencing and RNA silencing. The results demonstrated that surgery induced neurotoxic astrocyte reactivation, which contributed to the development of PNDs by C3-mediated microglial synaptic engulfment. Thus, C3 could be a potential therapeutic target for PNDs. 
Moreover, aged surgical mice did not have neuroinflammatory responses but displayed significant disruption of the blood-brain barrier with GLUT1 downregulation. To investigate the role of GLUT1 in the blood-brain barrier in PNDs, this project further evaluated the changes of metabolites in the hippocampus and examined their association with cognitive impairment by GC-MS technology and conditional overexpression of GLUT1 in the blood-brain barrier. The results illustrated that surgery-induced GLUT1 downregulation in the blood-brain barrier led to a decrease in glycolytic metabolites, which contributed to postoperative cognitive deficits.
In conclusion, this project provides a new interpretation of the pathological mechanism in PNDs and observes several potential targets for the therapeutic treatment of PNDs, which is worthy of further investigation.

术后神经功能障碍（PNDs）现象已为世人所熟知数十年，它不仅降低了患者的生活质量，延缓了康复进程，还对个人及社区带来了沉重的医疗负担。鉴于日益增长的人口接受手术，其中超过三分之一为老年患者，这种常见的术后并发症已成为社会面临的一项重大挑战。既往研究表明，神经炎症和血脑屏障破坏是PNDs中的两种关键病理变化，然而其潜在机制尚不明确，这为寻找潜在的药物治疗靶点带来了困难。

为阐释神经炎症与认知功能之间的关联，本项目首先探讨了术后反应性星形胶质细胞的特征，并利用RNA测序和RNA沉默技术，搜寻导致认知障碍的关键分泌因子。研究结果表明，手术引发的神经毒性星形胶质细胞再激活，通过C3介导的小胶质细胞突触吞噬作用，促进了PNDs的发展。因此，C3可能成为治疗PNDs的潜在靶点。

此外，老年手术小鼠未表现出神经炎症反应，但显示出血脑屏障的显著破坏和GLUT1的下调。为了研究GLUT1在PNDs中血脑屏障的作用，本项目进一步评估了海马区代谢物的变化，并通过GC-MS技术和条件性过表达血脑屏障中的GLUT1，考察了这些变化与认知障碍的相关性。结果表明，手术诱导的血脑屏障GLUT1下调导致糖酵解代谢物的减少，进而引发了术后认知缺陷。

总之，本项目对PNDs的病理机制提出了新的解释，并观察到了多个PNDs治疗治疗的潜在靶点，这些发现值得进一步深入研究。