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

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 microglia and interstitials space in the hippocampi of the mice developed POCD at all indicated time points after surgery. Significantly lower levels of peripheral TTR were also found in human patients that displayed impaired cognition after abdominal surgeries, 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. C57BL/6J mice aged 16 months underwent Y maze and open field experiment 24 hours before surgery, then underwent abdominal and small intestinal restoration, and then underwent Y maze and open field experiment with environmental parameters at 24 hours(24hps), 3 days(3dps), 7 days(7dps), and 1 month(1mps) after surgery, respectively. After behavioral experiment, the mice were anesthetized, and hippocampal tissues were collected after perfusion. Control mice did not undergo surgery. Progressive transcriptome sequencing of hippocampal tissue was performed in mice diagnosed with POCD and in control mice.