Therapeutic targets for the Allan-Herndon-Dudley Syndrome

Blood-brain barrier endothelial cells as therapeutic targets for the Allan-Herndon-Dudley Syndrome

The research group on Thyroid Hormones and the Central Nervous System, led by Dr. Ana Guadaño Ferraz at the Institute of Biomedical Research Sols-Morreale (CSIC-UAM), has described a new pathophysiological mechanism involved in the Allan-Herndon-Dudley Syndrome: the disruption of the blood-brain barrier.

The Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency is a rare disease caused by inactivating mutations in the monocarboxylate transporter 8 (MCT8). MCT8 is the primary thyroid hormone-specific transporter present in the human blood-brain barrier (BBB), the primary brain barrier in the regulation of the trafficking of molecules between peripheral blood and the brain parenchyma. MCT8 deficiency causes alterations in the levels of thyroid hormones in the patients' brains, resulting in severe cerebral hypothyroidism. This study demonstrates that MCT8 deficiency also causes structural and functional changes in endothelial cells and other components of the BBB, contributing to the progression of the disease by hindering the maintenance of cerebral homeostasis.

This work, recently published in the journal "Fluids and Barriers of the CNS," reveals alterations in the ultrastructure of neurovascular junctions (the structural unit of the BBB) in the capillaries of the cerebral cortex. "Additionally, we observed an increase in the BBB's permeability to impermeable dyes that normally do not penetrate the brain parenchyma, as well as an increase in the number of cerebral microhemorrhages and alterations in the primary angiogenic factors," Marina Guillén-Yunta, the first author of this article, shares.

This study has been conducted in a murine model of MCT8 deficiency (Mct8/Dio2KO). Post-mortem samples of brain tissue from an AHDS patient have also been used, "unique and of great value", adds Dr. Guadaño, where an increase in the BBB's permeability to peripheral IgG and a decrease in cerebral blood vessel density were observed. These findings were replicated in adult MCT8-deficient mice.

This pioneering work opens the door to studying the relevance of BBB integrity in disease progression, the importance of the MCT8 transporter in the basal physiology of the endothelial cell and neurovascular junction, as well as the consideration of this pathophysiological mechanism in the application of therapies targeted at the administration of thyroid hormones or their analogs through the BBB. Additionally, these results demonstrate the validity of non-invasive imaging techniques such as angiography as a biomarker for evaluating disease progression and treatment effectiveness.

This work also involved collaboration with Dr. José Manuel García Verdugo from the University of Valencia and CIBERNED and Dr. Guadalupe Soria from the Institute of Neuroscience at the University of Barcelona.

The image shows a three-dimensional reconstruction of the brain vasculature obtained through magnetic resonance angiography in a control mouse (left pane) and an Mct8/Dio2KO mouse (right panel).