Endocrine Abstracts

Background: The monocarboxylate transporter 8 (MCT8) is a transmembrane thyroid hormone-specific transporter expressed at the brain barriers, as the blood-brain barrier (BBB) and in neural cells, with a key role in maintaining cerebral thyroid hormone homeostasis. Inactivating mutations in the MCT8 gene (SLC16A2) lead to the developmental rare X-linked disease known as MCT8 Deficiency or Allan-Herndon-Dudley Syndrome (AHDS). This disease is characterized by peripheral hyperthyroidism, delayed neurodevelopment, hypomyelination, and severe psychomotor disorders. The underlying pathophysiological mechanisms of AHDS remain unclear, with a lack of effective treatments available for the neurological condition of the disease, being the bypass of the MCT8-deficient BBB the main therapeutic challenge for the delivery of thyroid hormone-related drugs. Thus, the study aimed to evaluate the integrity and permeability of the BBB in conditions of MCT8 Deficiency.

Methods: Neurovascular unit ultrastructure was studied by transmission electron microscopy and pericytes were studied by immunofluorescence. BBB permeability and integrity were analyzed by immunohistochemistry, BBB non-permeable dye infiltration assays, and histological microhemorrhage-staining techniques. Brain blood vessel density was evaluated by blood vessel fluorolabeling and in vivo magnetic resonance angiography. Finally, angiogenic-related factors expression was studied by qRT-PCR. The studies were carried out both in an MCT8-deficient subject and in Mct8/Dio2 KO mice, a murine model for AHDS, and their respective controls.

Results: Ultrastructural analysis of the BBB of Mct8/Dio2 KO mice revealed significant alterations in neurovascular unit integrity, increased transcytotic flux, and edematous perivascular astrocytes. No qualitative changes were observed in the pericyte population. We also found functional alterations in BBB permeability, as shown by an increased IgG infiltration, as well as increased infiltration of the non-permeable dyes Sodium Fluorescein and Evans Blue, along with increased presence of brain microhemorrhages. We also observed alterations in angiogenesis, with reduced blood vessel density in adult mice and altered expression of angiogenesis-related factors during BBB development. Similarly, the human MCT8-deficient brain showed increased BBB permeability to IgG and decreased blood vessel density.

Conclusions: These findings represent a novel pathophysiological mechanism for MCT8 Deficiency, revealing a disruption in the BBB integrity and functionality and neurovascular unit ultrastructural alterations. These results open a new field for potential therapeutic targets for the neurological symptoms of the disease and unveil magnetic resonance angiography as a new non-invasive in vivo technique for disease progression evaluation.