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Transthyretin, a novel prognostic marker of POCD revealed by time-series RNA-sequencing analysis

Molecular Psychiatry volume 30, pages 3103–3119 (2025)Cite this article

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Abstract

Postoperative cognitive dysfunction (POCD) is defined as a declined cognition, measured by neuropsychological tests, that persists for months or even longer after surgery. Heterogeneities in the diagnosis of POCD usually involve differences in the test batteries, the cutoffs, and the timing of assessments. Although peripheral and CSF markers of neuroinflammation have been shown to correlate with increased risk of POCD, most of them are non-specific and cannot be used for POCD diagnosis. These factors hampered the understanding of the pathogenesis of POCD as well as the development of effective preventions/treatments. In this study, we found Ttr in a panel of potential POCD biomarkers identified using time-series analysis of the transcriptomes and proteomes of the hippocampi of POCD mice that diagnosed on individual basis with composite Z-scores of test batteries consisting of Y maze and open field test. Compared with their counterparts without POCD, the levels of Ttr were significantly lower in the peripheral circulation as well as in the hippocampi of the mice developed POCD at all indicated time points after surgery. The levels of peripheral TTR in human patients with delayed neurocognitive recovery were found to be reduced at 24 h after abdominal surgery, compared with those who did not. Endogenous expression of Ttr was verified in microglia cells both in vitro and in vivo. Results of in vitro assay indicated a potential role of Ttr in ameliorating LPS-induced microglial priming and protecting the differentiation of oligodendrocyte progenitor cells (OPCs) in proinflammatory microenvironment, which was one of the determinant factors in regulating the pathological progression of POCD.

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Fig. 1: Individual-based mouse behavioral assessment and defining POCD in mice.
Fig. 2: Pattern of changes in gene expression reflects the pathological progression of POCD.
Fig. 3: Time course clustering of DEGs and the associated enrichment analysis of gene functions.
Fig. 4: The expression of TTR was persistently reduced in the serum and in the hippocampal tissue samples of POCD.
Fig. 5: The expression of endogenous TTR was reduced in LPS-induced microglia.
Fig. 6: Persistently reduced Ttr expression caused impaired myelination under propagated neuroinflammation in POCD.

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Data availability

The datasets used in this study are available from the corresponding author on reasonable request. The raw data are available via GEO with the accession number GSE276942.

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Acknowledgements

This work was sponsored by the Guangdong Provincial Key R&D Program of Department of Natural Resources of Guangdong Province (#2023B1111050011) and the Natural Science Foundation of Guangdong (#2023A1515010293).

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  1. These authors contributed equally: Xiaosheng Liang, Chao Song, Jingrun Lin.

Authors and Affiliations

  1. School of life science and technology, Jinan University, Guangzhou, 510632, China

    Xiaosheng Liang, Chao Song, Shufang Li, Linpeng Li, Guoku Dai, Ruohui Zhang, Olivia Meilan Zou, Hongyu Yao & Yi Zou

  2. Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non-human Primate Research, Guangzhou, 510632, China

    Xiaosheng Liang & Libing Zhou

  3. Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China

    Jingrun Lin

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Contributions

XL established the mouse model, performed western blot assay, bioinformatic analysis and data process. CS processed the sequencing data, conducted the ELISA assay and in vitro studies. JL conducted the clinical trial. SL performed immunohistology assay and Golgi staining. LL and GD performed the performed exosome isolation and uptake experiments. RZ performed qPCR and the image analysis. OMZ and HY assist mouse work and data processing. LZ helped data analysis. YZ supervised the project, conceived this research, drafted the paper, designed the experiment, and interpreted the data. YZ is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

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Correspondence to Yi Zou.

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The procedures involving animals were performed in accordance with the animal research committee of Jinan University and the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals. All animal experiments were approved by the Institutional Animal Care and Use Committee of Jinan University (IACUC-20230625-07). The clinical trial study was approved by the internal review and ethics boards of Sun Yat-sen Memorial Hospital (Approval No: 2022-KY–072, Registration No: ChiCTR2300069362). All methods were performed in accordance with the relevant guidelines and regulations.

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Liang, X., Song, C., Lin, J. et al. Transthyretin, a novel prognostic marker of POCD revealed by time-series RNA-sequencing analysis. Mol Psychiatry 30, 3103–3119 (2025). https://doi.org/10.1038/s41380-025-02918-0

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