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The Role of Thyroid Hormone in Neuronal Protection

Yan‐Yun Liu, Gregory A. Brent

10.1002/cphy.c200019

Source: Volume 11, Issue 3, July 2021

Published online: June 2021

Full Article on Wiley Online Library



Abstract

Thyroid hormone is essential for brain development and brain function in the adult. During development, thyroid hormone acts in a spatial and temporal‐specific manner to regulate the expression of genes essential for normal neural cell differentiation, migration, and myelination. In the adult brain, thyroid hormone is important for maintaining normal brain function. Thyroid hormone excess, hyperthyroidism, and thyroid hormone deficiency, hypothyroidism, are associated with disordered brain function, including depression, memory loss, impaired cognitive function, irritability, and anxiety. Adequate thyroid hormone levels are required for normal brain function. Thyroid hormone acts through a cascade of signaling components: activation and inactivation by deiodinase enzymes, thyroid hormone membrane transporters, and nuclear thyroid hormone receptors. Additionally, the hypothalamic‐pituitary‐thyroid axis, with negative feedback of thyroid hormone on thyrotropin‐releasing hormone (TRH) and thyroid‐stimulating hormone (TSH) secretion, regulates serum thyroid hormone levels in a narrow range. Animal and human studies have shown both systemic and local reduction in thyroid hormone availability in neurologic disease and after brain trauma. Treatment with thyroid hormone and selective thyroid hormone analogs has resulted in a reduction in injury and improved recovery. This article will describe the thyroid hormone signal transduction pathway in the brain and the role of thyroid hormone in the aging brain, neurologic diseases, and the protective role when administered after traumatic brain injury. © 2021 American Physiological Society. Compr Physiol 11:2075‐2095, 2021.

Figure 1. Figure 1. Thyroid hormones. The prohormone thyroxine (T4) is converted to the active hormone triiodothyronine (T3) by the Dio1 and Dio2 enzymes, 5′‐deiodinases, that remove an outer ring iodine. T4 can be inactivated by Dio3, 5‐deioiodinase, which removes an inner ring iodine and converts T3 to reverse T3 (rT3). Dio1, Dio2, and Dio3 are denoted as Deiodinases 1, 2, and 3.
Figure 2. Figure 2. Primary thyroid hormone transporters in the brain. A putative model of thyroid hormone signaling in the human brain based on the available studies. To exert its effects inside the brain, thyroid hormone needs to cross multiple barriers. This illustration provides a schematic overview of the different barriers in the human brain in which MCT8 and OATP1C1, and possibly additional transporters, might be involved in the transport of thyroid hormone. In most cases, definite proof of functional contribution to thyroid hormone transport is lacking. Moreover, the expression and contribution of the various thyroid hormone transporters likely depend on the developmental stage and vary between different cell populations of the same tissue. It is also unclear to what extent transporters other than those displayed here are expressed at the protein level at the different sites and contribute to thyroid hormone transport in the human brain. *LAT2 is localized to adult neurons and microglia but is absent in fetal neurons. Recently proposed novel routes by which thyroid hormone may enter the brain through the inner and outer cerebrospinal fluid brain barrier are not depicted. Abbreviations: 3V, third ventricle; BBB, blood‐brain‐barrier; BCSFB, blood‐cerebrospinal fluid barrier; CSF, cerebrospinal fluid; iTH, inactivated thyroid hormones. Reused, with permission, from Groeneweg S, et al., 2020 66.
Figure 3. Figure 3. Thyroid hormone receptor isoform‐specific functions. THRB1 and THRB2 are expressed in the brain and pituitary and mediate feedback from circulating thyroid hormone to regulate thyroid production by inhibiting expression of TRH in the hypothalamus and TSH in the pituitary. THRA1 is the primary THR expressed in the brain and accounts for 80% of the total THRs. THRA1 mediates T3 actions on brain development and function, as well as important actions of T3 in heart, skeletal muscle, brown adipose tissue, and bone.
Figure 4. Figure 4. Thyroid hormone effects on mitochondrial biogenesis. The schematic representation is drawn based on current knowledge of T3 action in skeletal muscle. T3 stimulates Pgc‐1α gene expression by direct binding to the Pgc‐1α gene and by nongenomic actions promoting AMPK/PI3K signaling. AMPK/PI3K phosphorylates, stabilizes, and activates the PGL‐1α protein, the master regulator of mitochondrial biogenesis. PGL‐1α binds the NRF1/2 gene promotor and actives Nrf1/2 gene transcription. NRF1/2, in turn, stimulates expression of the mitochondria transcription factor A (Tfam). T FAM protein is required for mitochondrial genome replication, repair, and mitochondrial gene transcription for biogenesis. T3 stimulates oxidative respiration and increases reactive oxygen species (ROS) and mitophagy.
Figure 5. Figure 5. Kaplan‐Meier survival curve of serum T3 levels of patients after an acute stroke. Patients with low serum T3, compared to patients with normal serum T3, followed for 12 months after an acute stroke. Adapted, with permission, from Alevizaki M, et al., 2007 5.
Figure 6. Figure 6. Thyroid hormone and adult neurogenesis in the dentate gyrus of subgranular zone (SGZ) in the hippocampus. (A) Sagittal view of the rodent brain with the boxed region outlining hippocampal formation. (B) Schematic of the hippocampus with CA1, CA3, dentate gyrus (DG), and hilus regions. (C). The SGZ niche is comprised of radial and horizontal type 1 NSCs (pink), early‐stage type 2a transit‐amplifying progenitors (TAPs) (orange), late‐stage type 3 TAPs/neuroblasts (yellow), immature granule neurons (green), and mature granule neurons (blue). The progression from NSCs to mature granule neurons in adult SGZ is a multistep process with distinct stages (labeled on top) and is controlled by the sequential expression of transcription factors (bottom colored panels). Neural stem cells (NSCs) receive the signal to proliferate and divide and generate TAPs, that are differentiated into neurons and astrocytes. Type 2a‐2b and neuroblasts are self‐renewing cells. A portion of these cells is differentiated. T3/THRA1 directly influences the differentiation of nonproliferating type 2b TPAs into type 3 neuroblasts, and then neuroblasts to immature neurons. T3/THRA1 also has a role in the maturation of immature granule neurons. The red bar indicates THRA1 expressed in all cell types. ML, molecular layer; GCL, granule cell layer. Adapted and modified, with permission, from Jenny Hsiegh, 2012.
Figure 7. Figure 7. Thyroid hormone regulates adult neurogenesis in the subventricular zone (SVZ). (A) Sagittal view of the rodent brain, with the boxed region outlining the SVZ region next to the lateral ventricle (LV). (B) Schematic of the SVZ with ependymal cells (E), blood vessel (BV) cells, and distinct stem/progenitor cell types (types B, C, and A). (C) The SVZ niche is comprised of astrocyte‐like type B1 and B2 NSCs (pink), type C TAPs (orange), type A neuroblasts (yellow), immature neurons (green), and mature neurons (blue). The progression from type B NSCs to mature neurons in the adult SVZ is a multistep process with distinct stages (labeled on top) and is controlled by the sequential expression of transcription factors (bottom colored panels). T3/THRA1 regulates differentiation of NSCs, progenitor cell proliferation, and commitment toward a neuronal phenotype in SVZ neurogenesis niche of adult brain. THRA1 is expressed in all neuronal cell types. T3 action is strongly indicated in differentiation. The shade of bars depicts the strength of influences. Adapted and modified, with permission, from Jenny Hsiegh, 2012.
Figure 8. Figure 8. Thyroid hormone protects hypoxic neuronal degradation via epigenetic pathways. The mouse primary cortical neurons are exposed to 0.2% hypoxia in the presence or absence of 5 mM T3. The epigenetic change is compared with controls for the mRNA level of DNA methyltransferases (Dnmts) and demethylation enzymes (Tets) and quantitative measurement of 5‐hydroxymethylcytosine (demethylation) and 5‐methylcytosine (methylated) as percentage of total DNA. Adapted, with permission, from Li J, et al., 2019 100.


Figure 1. Thyroid hormones. The prohormone thyroxine (T4) is converted to the active hormone triiodothyronine (T3) by the Dio1 and Dio2 enzymes, 5′‐deiodinases, that remove an outer ring iodine. T4 can be inactivated by Dio3, 5‐deioiodinase, which removes an inner ring iodine and converts T3 to reverse T3 (rT3). Dio1, Dio2, and Dio3 are denoted as Deiodinases 1, 2, and 3.


Figure 2. Primary thyroid hormone transporters in the brain. A putative model of thyroid hormone signaling in the human brain based on the available studies. To exert its effects inside the brain, thyroid hormone needs to cross multiple barriers. This illustration provides a schematic overview of the different barriers in the human brain in which MCT8 and OATP1C1, and possibly additional transporters, might be involved in the transport of thyroid hormone. In most cases, definite proof of functional contribution to thyroid hormone transport is lacking. Moreover, the expression and contribution of the various thyroid hormone transporters likely depend on the developmental stage and vary between different cell populations of the same tissue. It is also unclear to what extent transporters other than those displayed here are expressed at the protein level at the different sites and contribute to thyroid hormone transport in the human brain. *LAT2 is localized to adult neurons and microglia but is absent in fetal neurons. Recently proposed novel routes by which thyroid hormone may enter the brain through the inner and outer cerebrospinal fluid brain barrier are not depicted. Abbreviations: 3V, third ventricle; BBB, blood‐brain‐barrier; BCSFB, blood‐cerebrospinal fluid barrier; CSF, cerebrospinal fluid; iTH, inactivated thyroid hormones. Reused, with permission, from Groeneweg S, et al., 2020 66.


Figure 3. Thyroid hormone receptor isoform‐specific functions. THRB1 and THRB2 are expressed in the brain and pituitary and mediate feedback from circulating thyroid hormone to regulate thyroid production by inhibiting expression of TRH in the hypothalamus and TSH in the pituitary. THRA1 is the primary THR expressed in the brain and accounts for 80% of the total THRs. THRA1 mediates T3 actions on brain development and function, as well as important actions of T3 in heart, skeletal muscle, brown adipose tissue, and bone.


Figure 4. Thyroid hormone effects on mitochondrial biogenesis. The schematic representation is drawn based on current knowledge of T3 action in skeletal muscle. T3 stimulates Pgc‐1α gene expression by direct binding to the Pgc‐1α gene and by nongenomic actions promoting AMPK/PI3K signaling. AMPK/PI3K phosphorylates, stabilizes, and activates the PGL‐1α protein, the master regulator of mitochondrial biogenesis. PGL‐1α binds the NRF1/2 gene promotor and actives Nrf1/2 gene transcription. NRF1/2, in turn, stimulates expression of the mitochondria transcription factor A (Tfam). T FAM protein is required for mitochondrial genome replication, repair, and mitochondrial gene transcription for biogenesis. T3 stimulates oxidative respiration and increases reactive oxygen species (ROS) and mitophagy.


Figure 5. Kaplan‐Meier survival curve of serum T3 levels of patients after an acute stroke. Patients with low serum T3, compared to patients with normal serum T3, followed for 12 months after an acute stroke. Adapted, with permission, from Alevizaki M, et al., 2007 5.


Figure 6. Thyroid hormone and adult neurogenesis in the dentate gyrus of subgranular zone (SGZ) in the hippocampus. (A) Sagittal view of the rodent brain with the boxed region outlining hippocampal formation. (B) Schematic of the hippocampus with CA1, CA3, dentate gyrus (DG), and hilus regions. (C). The SGZ niche is comprised of radial and horizontal type 1 NSCs (pink), early‐stage type 2a transit‐amplifying progenitors (TAPs) (orange), late‐stage type 3 TAPs/neuroblasts (yellow), immature granule neurons (green), and mature granule neurons (blue). The progression from NSCs to mature granule neurons in adult SGZ is a multistep process with distinct stages (labeled on top) and is controlled by the sequential expression of transcription factors (bottom colored panels). Neural stem cells (NSCs) receive the signal to proliferate and divide and generate TAPs, that are differentiated into neurons and astrocytes. Type 2a‐2b and neuroblasts are self‐renewing cells. A portion of these cells is differentiated. T3/THRA1 directly influences the differentiation of nonproliferating type 2b TPAs into type 3 neuroblasts, and then neuroblasts to immature neurons. T3/THRA1 also has a role in the maturation of immature granule neurons. The red bar indicates THRA1 expressed in all cell types. ML, molecular layer; GCL, granule cell layer. Adapted and modified, with permission, from Jenny Hsiegh, 2012.


Figure 7. Thyroid hormone regulates adult neurogenesis in the subventricular zone (SVZ). (A) Sagittal view of the rodent brain, with the boxed region outlining the SVZ region next to the lateral ventricle (LV). (B) Schematic of the SVZ with ependymal cells (E), blood vessel (BV) cells, and distinct stem/progenitor cell types (types B, C, and A). (C) The SVZ niche is comprised of astrocyte‐like type B1 and B2 NSCs (pink), type C TAPs (orange), type A neuroblasts (yellow), immature neurons (green), and mature neurons (blue). The progression from type B NSCs to mature neurons in the adult SVZ is a multistep process with distinct stages (labeled on top) and is controlled by the sequential expression of transcription factors (bottom colored panels). T3/THRA1 regulates differentiation of NSCs, progenitor cell proliferation, and commitment toward a neuronal phenotype in SVZ neurogenesis niche of adult brain. THRA1 is expressed in all neuronal cell types. T3 action is strongly indicated in differentiation. The shade of bars depicts the strength of influences. Adapted and modified, with permission, from Jenny Hsiegh, 2012.


Figure 8. Thyroid hormone protects hypoxic neuronal degradation via epigenetic pathways. The mouse primary cortical neurons are exposed to 0.2% hypoxia in the presence or absence of 5 mM T3. The epigenetic change is compared with controls for the mRNA level of DNA methyltransferases (Dnmts) and demethylation enzymes (Tets) and quantitative measurement of 5‐hydroxymethylcytosine (demethylation) and 5‐methylcytosine (methylated) as percentage of total DNA. Adapted, with permission, from Li J, et al., 2019 100.
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Article Title: The Role of Thyroid Hormone in Neuronal Protection
 

How to Cite

Yan‐Yun Liu, Gregory A. Brent. The Role of Thyroid Hormone in Neuronal Protection. Compr Physiol 2021, 11: 2075-2095. doi: 10.1002/cphy.c200019