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Transthyretin Regulates Thyroid Hormone Levels in the Choroid Plexus, But Not in the Brain Parenchyma: Study in a Transthyretin-Null Mouse Model¹

Unidade de Amilóide, Instituto de Biologia Molecular e Celular (J.A.P., R.F., M.J.S.), 4150–180 Porto, Portugal; Instituto Superior de Ciências da Saúde-Norte (J.A.P.), 4585-116 Gandra, Portugal; Unidad de Endocrinologia Molecular, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid (G.M.D.E.), 28029 Madrid, Spain; Medical Research Council Clinical Sciences Center, Mammalian Neurogenesis Laboratory, Hammersmith Hospital (V.E.), W12 ONN London, United Kingdom; Institute of Cancer Research, Columbia University (M.G.), New York, New York 10032; and Instituto de Ciências Biomédicas Abel Salazar (M.J.S.), 4099-003 Porto, Portugal

Address all correspondence and requests for reprints to: Dr. Joana Almeida Palha, Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150–180 Porto, Portugal. E-mail: japalha{at}ibmc.up.pt

Transthyretin (TTR) is the major T₄-binding protein in rodents. Using a TTR-null mouse model we asked the following questions. 1) Do other T₄ binding moieties replace TTR in the cerebrospinal fluid (CSF)? 2) Are the low whole brain total T₄ levels found in this mouse model associated with hypothyroidism, e.g. increased 5'-deiodinase type 2 (D2) activity and RC3-neurogranin messenger RNA levels? 3) Which brain regions account for the decreased total whole brain T₄ levels? 4) Are there changes in T₃ levels in the brain? Our results show the following. 1) No other T₄-binding protein replaces TTR in the CSF of the TTR-null mice. 2) D2 activity is normal in the cortex, cerebellum, and hippocampus, and total brain RC3-neurogranin messenger RNA levels are not altered. 3) T₄ levels measured in the cortex, cerebellum, and hippocampus are normal. However T₄ and T₃ levels in the choroid plexus are only 14% and 48% of the normal values, respectively. 4) T₃ levels are normal in the brain parenchyma. The data presented here suggest that TTR influences thyroid hormone levels in the choroid plexus, but not in the brain. Interference with the blood-choroid-plexus-CSF-TTR-mediated route of T₄ entry into the brain caused by the absence of TTR does not produce measurable features of hypothyroidism. It thus appears that TTR is not required for T₄ entry or for maintenance of the euthyroid state in the mouse brain.

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