TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor

Ferrara, Skylar J.; Chaudhary, Poras; DeBell, Margaret J.; Marracci, Gail; Miller, Hannah; Calkins, Evan; Pocius, Edvinas; Napier, Brooke A.; Emery, Ben; Bourdette, Dennis; Scanlan, Thomas S.

doi:10.1016/j.chembiol.2021.07.014

“…The association of TYROBP with sporadic and early-onset AD and its role as a key regulator for many AD-associated functions of microglia, including phagocytosis, complement activation, synaptic pruning, and a switch from homeostatic to DAM state, suggest that the modulation of TYROBP level or activity may represent a therapeutic opportunity in AD. Although the potential “druggability” of microglial receptors and adapters such as TYROBP may present challenges due to the interactions of each with numerous ligands and signaling pathways, the recent discovery of CNS-penetrating small molecules like sobetirome and Sob-AM2, two thyromimetic agents capable of targeting TREM2, may ultimately lead to a viable therapeutic approach to selective manipulation of individual microglial events [ 140 ]. Overall, a better understanding of TYROBP and its many interactors and pathways will improve our understanding of the role(s) played by microglia in the etiology and pathogenesis of human neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Microglial TYROBP/DAP12 in Alzheimer’s disease: Transduction of physiological and pathological signals across TREM2

Haure‐Mirande

¹

,

Audrain

²

,

Ehrlich

³

et al. 2022

Mol Neurodegeneration

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TYROBP (also known as DAP12 or KARAP) is a transmembrane adaptor protein initially described as a receptor-activating subunit component of natural killer (NK) cells. TYROBP is expressed in numerous cell types, including peripheral blood monocytes, macrophages, dendritic cells, and osteoclasts, but a key point of recent interest is related to the critical role played by TYROBP in the function of many receptors expressed on the plasma membrane of microglia. TYROBP is the downstream adaptor and putative signaling partner for several receptors implicated in Alzheimer’s disease (AD), including SIRP1β, CD33, CR3, and TREM2. TYROBP has received much of its current notoriety because of its importance in brain homeostasis by signal transduction across those receptors. In this review, we provide an overview of evidence indicating that the biology of TYROBP extends beyond its interaction with these four ligand-binding ectodomain-intramembranous domain molecules. In addition to reviewing the structure and localization of TYROBP, we discuss our recent progress using mouse models of either cerebral amyloidosis or tauopathy that were engineered to be TYROBP-deficient or TYROBP-overexpressing. Remarkably, constitutively TYROBP-deficient mice provided a model of genetic resilience to either of the defining proteinopathies of AD. Learning behavior and synaptic electrophysiological function were preserved at normal physiological levels even in the face of robust cerebral amyloidosis (in APP/PSEN1;Tyrobp−/− mice) or tauopathy (in MAPTP301S;Tyrobp−/− mice). A fundamental underpinning of the functional synaptic dysfunction associated with each proteotype was an accumulation of complement C1q. TYROBP deficiency prevented C1q accumulation associated with either proteinopathy. Based on these data, we speculate that TYROBP plays a key role in the microglial sensome and the emergence of the disease-associated microglia (DAM) phenotype. TYROBP may also play a key role in the loss of markers of synaptic integrity (e.g., synaptophysin-like immunoreactivity) that has long been held to be the feature of human AD molecular neuropathology that most closely correlates with concurrent clinical cognitive function.

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“…At the gene level, the study of thyroid hormones and immune cells has gradually increased. TREM2, its expression in macrophages and microglia, is stimulated by thyroid hormone [ 33 ]. Thyroid hormone agonism was also found to induce phagocytic behavior in microglia consistent with the TREM2 pathway.…”

Section: Discussionmentioning

confidence: 99%

Thyroid Hormone Changes in the Northern Area of Tianjin during the COVID-19 Pandemic

Dong

¹

,

Wu

²

,

Wang

³

et al. 2022

International Journal of Endocrinology

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Purpose. This study aimed to determine whether and how stress-induced thyroid hormone changes occur during the COVID-19 pandemic in the northern area of Tianjin. Methods. This study comprised two groups of study subjects in Tianjin: before (2019) and during (2020) the COVID-19 outbreak. Subjects were included if they had FT3, FT4, and TSH concentrations and thyroid TPOAb or TgAb information available. People who were pregnant, were lactating, or had mental illness were excluded. We used propensity score matching to form a cohort in which patients had similar baseline characteristics, and their anxiety level was measured by the Hamilton Anxiety Rating Scale (HAMA). Results. Among the 1395 eligible people, 224 in Group A and 224 in Group B had similar propensity scores and were included in the analyses. The detection rate of abnormal thyroid function was decreased in pandemic Group B (69.2% vs. 93.3%, χ2 = 42.725, p < 0.01 ), especially for hypothyroidism (14.29% vs. 35.71%, χ2 = 27.429, p < 0.01 ) and isolated thyroid-related antibodies (25.89% vs. 38.39%, χ2 = 8.023, p < 0.01 ). The level of FT4 (z = −2.821, p < 0.01 ) and HAMA score (7.63 ± 2.07 vs. 5.40 ± 1.65, t = 16.873, p < 0.01 ) went up in Group B; however, TSH (z = −5.238, p < 0.01 ), FT3 (z = −3.089, p = 0.002 ), TgAb (z = −11.814, p < 0.01 ), and TPOAb (z = −9.299, p < 0.01 ) were lower, and HAMA was positive with FT3 (r = 0.208, p < 0.01 ) and FT4 (r = 0.247, p < 0.01 ). Conclusion. People in the northern area of Tianjin during the COVID-19 outbreak were at an increased risk of higher FT4, lower FT3, and lower TSH. The HAMA scores increased in emergency situations and were positively correlated with the levels of FT3 and FT4.

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“…Furthermore, TREM2 is crucial in osteoclastogenesis within PD microenvironment [ 31 ]. TREM2 is regulated by thyroid hormones [ 32 ]. Thus, the relationship between PD and HT based on bone metabolism appears plausible.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis Reveals Genetic Cross-Talk between Periodontitis and Hypothyroidism

Yan

¹

,

Ren

²

,

Shang

³

et al. 2022

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Background. Aim of this bioinformatics study based on transcriptomic analysis was to reveal the cross-talk between periodontitis (PD) and hypothyroidism (HT). Methods. The gene expression datasets GSE18152 and GSE176153 of HT and GSE10334, GSE16134, and GSE173078 of PD were downloaded through the Gene Expression Omnibus (GEO) database. Differential Expression Genes (DEG) between cases and controls in each microarray were assessed by using the “limma” (linear models for microarray data) R package (|log2 fold change (FC)| >0 and P -value <0.05). To analyze the cross-talk effect between HT and PD, the intersection of DEG of HT and PD was selected. To investigate the biological function of cross-talk genes, the gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied. Protein-Protein Interaction (PPI) network was constructed using Cytoscape software. Top 10 cross-talk genes were screened, and the expression values of these 10 genes were extracted. ROC analysis was performed by using the pROC package and GGplot2 package of R language to predict the classification accuracy. Results. The overlapping DEG between HT and PD were 107 cross-talk genes. The results revealed that developmental process ( P -value =1.06E-21) was the most significantly enriched biological process, followed by cell differentiation ( P -value =8.49E-18) and immune system process ( P -value =6.78E-11). KEGG analysis showed that Complement and coagulation cascades ( P -value =2.29E-05), Hematopoietic cell lineage ( P -value =2.66E-05), Phospholipase D signaling pathway ( P -value =0.034367878) and Chemokine signaling pathway ( P -value =0.04946333) were significantly enriched. The top 10 genes with most connections were LCE1B, LCE2B, LCE2A, LCE2C, LCE1C, LCE1F, ITGAM, C1QB, TREM2, and CD19. The AUC values of the two datasets of HT were both greater than 65% (GSE18152 = 81.42%, GSE176153 = 68.75%). AUC values of three datasets of PD were all greater than 60% (GSE10334 = 69.23%, GSE16134 = 73.72%, GSE173078 = 81.6%). Conclusions. A genetic cross-talk between HT and PD was detected, whereby LCE family genes appeared to play the most important role.

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TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor

Cited by 14 publications

References 78 publications

Microglial TYROBP/DAP12 in Alzheimer’s disease: Transduction of physiological and pathological signals across TREM2

Microglial TYROBP/DAP12 in Alzheimer’s disease: Transduction of physiological and pathological signals across TREM2

Thyroid Hormone Changes in the Northern Area of Tianjin during the COVID-19 Pandemic

Transcriptomic Analysis Reveals Genetic Cross-Talk between Periodontitis and Hypothyroidism

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