It has been shown that transthyretin (TTR), which is synthesised and secreted by the choroid plexus (CP), binds avidly to thyroxine (T4) and might be responsible for the concentration of T4 being higher in the CSF than plasma (Schreiber et al. 2001). We have shown in a previous study that TTR when complexed with T4 increases the uptake of T4 into brain tissues (Kassem et al. 2002), but at the cellular level the mechanism by which this protein complex enters the brain is not clear. Kuchler-Bopp et al. (2000) have demonstrated that the TTR receptors are expressed on ependymoma cells and it has been suggested that the ependyma may act as a reservoir for T4.

By using the ventriculo-cisternal perfusion (VC) technique in anaesthetized rabbits (Domitor and pentobarbitone given I.V. at a dose of 0.5 mg and 10 mg kg^-1, respectively; at the end of the experiment the animals were humanely killed), we have investigated the effect of endocytosis inhibitors on the brain uptake and loss of TTR as ¹²⁵I-TTR-T4 complex from the aCSF perfusate. Values are means ± S.E.M., and were compared with Student’s unpaired t test.

Nocodazole at 50 µM was added to the aCSF perfusate and the uptake of TTR-T4 complex into the caudate nucleus was significantly reduced from a control value of 49.2 ± 8.6 ml (100 g)^-1, to 23.0 ± 9.7 ml (100 g)^-1 (P < 0.05, n = 3). In the ependymal layer (EL) the control uptake was 38.6 ± 5.8 ml (100 g)^-1 (n = 5), while in the presence of nocodazole the uptake was significantly decreased to 6.9 ± 3.4 ml (100 g)^-1 (P < 0.01, n = 3). Similarly after the addition of 100 µM monensin to the aCSF, the uptake of the TTR-T4 complex into EL was reduced by 38.5 ± 7.0 ml (100 g)^-1 (P < 0.05, n = 3), a significant difference from the control. However both drugs had no effect on the loss of the complex from the aCSF.

We conclude that the uptake of TTR-T4 complex from the aCSF into brain is by a receptor-mediated endocytosis.

This work was partly funded by Al-Tajir World of Islam Trust.