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Transforming Growth Factor β1 Ameliorates Microglial Activation in Perioperative Neurocognitive Disorders

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Abstract

Perioperative neurocognitive disorder (PND) is a common complication of surgery and anesthesia, especially among older patients. Microglial activation plays a crucial role in the occurrence and development of PND and transforming growth factor beta 1 (TGF-β1) can regulate microglial homeostasis. In the present study, abdominal surgery was performed on 12–14 months-old C57BL/6 mice to establish a PND model. The expression of TGF-β1, TGF-β receptor 1, TGF-β receptor 2, and phosphor-smad2/smad3 (psmad2/smad3) was assessed after anesthesia and surgery. Additionally, we examined changes in microglial activation, morphology, and polarization, as well as neuroinflammation and dendritic spine density in the hippocampus. Behavioral tests, including the Morris water maze and open field tests, were used to examine cognitive function, exploratory locomotion, and emotions. We observed decreased TGF-β1 expression after surgery and anesthesia. Intranasally administered exogenous TGF-β1 increased psmad2/smad3 colocalization with microglia positive for ionized calcium-binding adaptor molecule 1. TGF-β1 treatment attenuated microglial activation, reduced microglial phagocytosis, and reduced surgery- and anesthesia-induced changes in microglial morphology. Compared with the surgery group, TGF-β1 treatment decreased M1 microglial polarization and increased M2 microglial polarization. Additionally, surgery- and anesthesia-induced increase in interleukin 1 beta and tumor necrosis factor-alpha levels was ameliorated by TGF-β1 treatment at postoperative day 3. TGF-β1 also ameliorated cognitive function after surgery and anesthesia as well as rescue dendritic spine loss. In conclusion, surgery and anesthesia induced decrease in TGF-β1 levels in older mice, which may contribute to PND development; however, TGF-β1 ameliorated microglial activation and cognitive dysfunction in PND mice.

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Data Availability

The datasets used and/or analyzed in the present study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the assistance of the State Key Laboratory of Membrane Biology at Peking University in Beijing, China. We thank the assistance from the Central Core Facility of the National Center for Protein Sciences at Peking University, and Dr. Siying Qin at the Core Facilities of the School of Life Sciences, Peking University for assistance with optical/confocal imaging.

Funding

This study was supported by grand no. 82071176 from the National Science Foundation of China (NSFC), Beijing, China, grand no. 7222074 from the Beijing Natural Science Foundation, Beijing, China, and grand no. CYJZ202128 from Beijing Chao-Yang Hospital Golden Seeds Foundation. This study was supported by the NSFC general research grants (81971679), the National of Science and Technology Innovation 2030 (2022ZD0211800), and the Qidong-PKU SLS Innovation Fund (2016000663).

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  1. Changwei Wei, Anshi Wu and Yan Zhang have contributed equally to this work and share corresponding author.

Authors and Affiliations

  1. Department of Anesthesiology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongti Nanlu, Chao-Yang District, Beijing, 100020, China

    Dandan Lin, Yi Sun, Yuzhu Wang, Di Yang, Xiao Huang, Anshi Wu & Changwei Wei

  2. Department of Anesthesiology, Sichuan Provincial People’s Hospital, Sichuan Academy of Medical Sciences, University of Electronic Science and Technology of China, Chengdu, China

    Min Shui

  3. State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, 100871, China

    Yiming Wang & Yan Zhang

  4. Department of Anesthesiology, Peking University First Hospital, Beijing, China

    Ziyi Xue

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Contributions

Study design, C. W, A. W, Z.Y, and D.L; Performed research, D. L, D. Y, S.Y, Y. W; Data analyzed, M. S, Z. X; Writing-Original draft preparation, D. L, D. Y; Writing-review & editing, S.Y, Y. W, C.W, A. W; Supervision, C.W, A. W, Z.Y; Funding acquisition, Y. S, Y. Z, A. W. The final manuscript was approved by all authors.

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Correspondence to Yan Zhang, Anshi Wu or Changwei Wei.

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Supplementary Fig. 1 TGF-β1 level on postoperative day 1, 3, and 7. (A) Representative images from western blotting of TGF-β1. (B) Quantification of TGF-β1. n = 3. Data are shown as mean ± SEM. *p < 0.05. POD, postoperative day. Supplementary Fig. 2 Lamp1 level on postoperative day 3. (A) Representative images from western blotting of Lamp1 in hippocampus. (B) Quantification of Lamp1. n = 6. Data are shown as mean ± SEM. *p < 0.05; **p < 0.01. Supplementary Fig. 3 CD16/32 and CD206 level on postoperative day 3. (A) Representative images from western blotting of CD16/32 and CD206 in hippocampus. (B) Quantification of CD206. (C) Quantification of CD16/32. n = 6. Data are shown as mean ± SEM. *p < 0.05; **p < 0.01.

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Lin, D., Sun, Y., Wang, Y. et al. Transforming Growth Factor β1 Ameliorates Microglial Activation in Perioperative Neurocognitive Disorders. Neurochem Res 48, 3512–3524 (2023). https://doi.org/10.1007/s11064-023-03994-w

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