MCT8 Transporter Maps in Aged Human Brain

Researchers at the University of Leipzig have published a comprehensive anatomical map of the thyroid hormone transporter MCT8 in the adult and aged human brain. The study, published in Acta Neuropathologica Communications, systematically characterized the distribution of MCT8 across eight distinct brain regions using a multiscale approach. By combining immunostaining, automated whole-slide image analysis, multiplex RNAscope in situ hybridization, stimulated emission depletion (STED) microscopy, and single-nucleus RNA sequencing, the team identified where MCT8 is expressed and how it is preserved in the presence of neurofibrillary pathology associated with Alzheimer’s disease.

The local availability of thyroid hormones in the brain depends on specific transporters, with MCT8 being particularly important due to its high specificity for these hormones. Mutations in the SLC16A2 gene, which encodes MCT8, cause Allan-Herndon-Dudley syndrome, a condition marked by severe neurodevelopmental and motor deficits. While the role of MCT8 in fetal brain development is well established, its precise topographical and cellular distribution in the adult human brain had remained largely uncharacterized. This gap in knowledge limited understanding of which brain structures rely on MCT8-mediated transport throughout life and whether neurodegenerative processes affect local transporter availability.

To address this, the researchers analyzed tissue from 14 aged human body donors, with an age range of 64 to 101 years. The study focused on eight functionally distinct brain regions, including the primary motor cortex, cerebellum, occipital cortex, frontal and temporal cortex, hippocampus, hypothalamus, and medulla oblongata. These regions were selected to represent complementary functional systems such as motor function, sensory processing, higher-order association, learning and memory, and homeostatic regulation. The tissue samples were processed using fresh-frozen or paraffin-embedded methods to optimize MCT8 staining performance, with the polyclonal N-terminal antibody selected for its strong and consistent signal in regional and cellular distribution analyses.

The automated whole-slide image analysis classified over 13 million cells across 78 slides, allowing for a detailed quantification of MCT8 expression in neuronal and non-neuronal populations. The results demonstrated robust MCT8 expression across brain barriers, including endothelial cells, perivascular cells, astrocytes, choroid plexus epithelial cells, and tanycytes lining the third ventricle. In non-neuronal cells, MCT8 expression was lowest in the hypothalamus and hippocampal region, while it was highest in the frontal and occipital cortex. This compartment-specific variation suggests that regional differences in MCT8 expression are not uniform across all cell classes, with the occipital cortex showing high non-neuronal but low neuronal expression.

In neuronal populations, MCT8 expression was highest in the motor cortex and medulla oblongata, and lowest in the cerebellum and occipital cortex. The motor cortex exhibited large, layer V neurons with triangular somata and prominent apical dendrites that showed intense MCT8 immunoreactivity. These morphological features are consistent with pyramidal projection neurons, which are critical for voluntary motor function. The medulla oblongata, a region vital for motor output and autonomic regulation, also displayed one of the highest proportions of MCT8-expressing neurons. This widespread expression in motor and autonomic centers provides an anatomical framework for understanding the motor and cognitive impairments observed in individuals with MCT8 deficiency.

Subcellular localization of MCT8 was further resolved using STED microscopy, which revealed that the transporter is not only present at the plasma membrane but also near or at the nuclear lamina. The mean distance between MCT8 and Lamin B1 signals was measured at 30.7 nanometers, indicating a close spatial association with the nuclear envelope. This finding supports the hypothesis that MCT8 plays a role in both transmembrane and intracellular thyroid hormone transport, potentially facilitating the delivery of hormones to and into the nucleus. RNAscope analysis confirmed a strong concordance between SLC16A2 mRNA presence and MCT8 immunoreactivity, validating the protein-level findings at the transcript level.

The study also investigated whether Alzheimer’s disease progression correlates with alterations in MCT8 expression by applying standardized Braak staging to the donor cohort. Donors were categorized into control and Alzheimer’s disease groups based on the extent of neurofibrillary degeneration. Statistical comparisons between the groups revealed no significant differences in MCT8 expression, regardless of the cell class analyzed. MCT8 expression was preserved across Braak stages, with no significant difference between donors with varying degrees of neurofibrillary pathology. This stability suggests that cerebral thyroid hormone dysregulation in Alzheimer’s disease likely reflects altered hormone metabolism rather than a loss of the MCT8 transporter itself.

Single-nucleus RNA sequencing data from the Allen Brain Cell Atlas further corroborated the histological findings, showing broad SLC16A2 expression across various neuronal and non-neuronal cell types. Microglia were the only cell type essentially devoid of SLC16A2 signal, aligning with previous reports that human microglia express the alternative transporter OATP1C1 rather than MCT8. Among neurons, glutamatergic and GABAergic populations showed comparable proportions of SLC16A2 expression, with peaks in the hippocampus and thalamus. Modulatory neuronal classes, including histaminergic, serotonergic, and dopaminergic neurons, also expressed SLC16A2 within their anatomical distributions, highlighting the diverse cellular roles of this transporter.

The hippocampal formation displayed a particularly complex pattern of MCT8 expression, with robust signals in the dentate gyrus granular cell layer and the polymorphic layer. Triangular-shaped neurons in the polymorphic layer, morphologically consistent with mossy cells, exhibited strong MCT8 signals across their plasma membranes. These cells are involved in neuroplasticity and pattern separation, processes vital for episodic memory formation. The presence of MCT8 in these regions suggests a potential link to thyroid hormone-dependent neurogenesis and synaptic plasticity, although the exact functional implications in the aged human brain remain to be fully elucidated.

Several limitations of the study were noted by the authors, including the relatively narrow age range of the post-mortem cohort, which restricts extrapolation to younger adults or developmental periods. The Braak-stratified comparison was limited by small subgroup sizes, which may have reduced the power to detect subtle changes in MCT8 expression. Additionally, the study did not include the subventricular zone, a critical neurogliogenic niche, and some cell-type-specific antibodies did not perform adequately in the fresh-frozen tissue. Despite these constraints, the study provides the first comprehensive anatomical map of MCT8 expression in the adult and aged human brain.

The findings establish that MCT8 forms a continuous anatomical route for thyroid hormone transport from the blood-brain barrier to individual parenchymal cells. The preservation of MCT8 expression in the presence of Alzheimer’s pathology indicates that the transporter is not a primary driver of thyroid hormone dysregulation in this disease. Instead, the data suggest that alterations in thyroid hormone levels in Alzheimer’s disease may result from changes in hormone metabolism or local conversion. This anatomical framework may help explain the multisystem neurological phenotype of MCT8 deficiency, including spasticity, parkinsonism, and dysautonomia, by identifying the specific brain regions and cell types that depend on MCT8-mediated transport.

The authors noted that investigating local MCT8 distribution in the subventricular zone and direct spatial transcriptomic validation of SLC16A2 in oligodendrocytes represent possibilities for future research. The current study provides a static snapshot of MCT8 distribution in aged tissue, which may not capture the temporal changes in expression that occur during disease progression. Nevertheless, the detailed characterization of MCT8 across multiple scales offers a valuable resource for understanding the physiological and pathological roles of thyroid hormone transport in the human brain.

Subject of Research: Multiscale characterization and distribution of the thyroid hormone transporter MCT8 in the adult and aged human brain

Article Title: Multiscale characterization and distribution of the thyroid hormone transporter MCT8 in the adult and aged human brain

Article References: Rotter, J., Kirmann, T., Brendler, J., Anthofer, L., Wilpert, N. M., Hallermann, S., Biebermann, H., & Bechmann, I. (2026). Multiscale characterization and distribution of the thyroid hormone transporter MCT8 in the adult and aged human brain. Acta Neuropathologica Communications, 14(1), Article 200. https://doi.org/10.1186/s40478-026-02435-3

Image Credits: AI Generated

DOI: 10.1186/s40478-026-02435-3

Keywords: Multiscale, characterization, distribution, thyroid, hormone, transporter, MCT8, adult, aged, human, brain, scientific research