Transthyretin as a Biomarker to Predict and Monitor Major Depressive Disorder Identified by Whole-Genome Transcriptomic Analysis in Mouse Models

Abstract

Background: Accumulations of stressful life events result in the onset of major depressive disorder (MDD). Comprehensive genomic analysis is required to elucidate pathophysiological changes and identify applicable biomarkers. Methods: Transcriptomic analysis was performed on different brain parts of a chronic mild stress (CMS)-induced MDD mouse model followed by systemic analysis. QPCR and ELISA were utilized for validation in mice and patients. Results: The highest numbers of genes with significant changes induced by CMS were 505 in the amygdala followed by 272 in the hippocampus (twofold changes; FDR, p < 0.05). Enrichment analysis indicated that the core-enriched genes in CMS-treated mice were positively enriched for IFN-γ response genes in the amygdala, and hedgehog signaling in the hippocampus. Transthyretin (TTR) was severely reduced in CMS-treated mice. In patients with diagnosed MDD, serum concentrations of TTR were reduced by 48.7% compared to controls (p = 0.0102). Paired samples from patients with MDD demonstrated a further 66.3% increase in TTR at remission compared to the acute phase (p = 0.0339). Conclusions: This study provides comprehensive information on molecular networks related to MDD as a basis for further investigation and identifies TTR for MDD monitoring and management. A clinical trial with bigger patient cohort should be conducted to validate this translational study.

The Wistar Kyoto Rat: A Model of Depression Traits

“…An additional argument for the relevance of abnormal HPT function in depression is the finding that MDD patients exhibit significantly reduced blood levels of transthyretin (TTR), the protein thought to be partially responsible for thyroxine transport across the blood brain barrier [ 139 ]. TTR has been recently identified as a novel biomarker not only for MDD diagnosis but also for disease monitoring [ 139 ].…”

“…An additional argument for the relevance of abnormal HPT function in depression is the finding that MDD patients exhibit significantly reduced blood levels of transthyretin (TTR), the protein thought to be partially responsible for thyroxine transport across the blood brain barrier [ 139 ]. TTR has been recently identified as a novel biomarker not only for MDD diagnosis but also for disease monitoring [ 139 ]. TTR is drastically reduced in the hippocampus of selectively-bred Wistar Kyoto More Immobile (WMI) males, who exhibit depression-like behaviors, unlike the control Wistar Kyoto Less Immobile (WLI) rats [ 94 ].…”

Inhibitory Neurons in Nucleus Tractus Solitarius Are Involved in Decrease of Heart Rate Variability and Development of Depression-Like Behaviors in Temporal Lobe Epilepsy

“…Excitatory and inhibitory neurons from related brain regions were identified by the expression of specific markers ( Figure 5A ) ( Morarach et al, 2021 ). DEGs, such as Hsp90aa1, Pcdh11x, Vwa5a, and Ttr, which have been linked to depression in previous studies, have been found ( Crow, 2011 ; Xiang et al, 2018 ; Szabo et al, 2021 ; Yu et al, 2021 ). In total, 5110 neurons in the above 4 groups were obtained and classified into 12 subtypes ( Figure 5B ) based on the expression of specific markers ( supplementary Table 4 ).…”

Freezing responses during prolonged threat memory retrieval reflect trait-like anxiety endophenotypes in female and male inbred mice

“…In addition to alterations in Bdnf , Ttr and Neurod2 expression implicated in MDD and autism spectrum disorder (ASD), respectively [45,46], we detected some other genes implicated in psychiatric disorders. For instance, En2 (engrailed 2), an ASD-associated gene [47,48], was upregulated in ACC of phasic responders more than fivefold.…”