Remember Me
Or use your Academic/Social account:


Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Chen, R; Chen, CP; Preston, JE (2016)
Publisher: Wiley
Languages: English
Types: Article
Subjects: Alzheimer's Disease, Thyroxine, TTR, CSF, RM, efflux, QP, R1, choroid plexus, β-amyloid
Transthyretin (TTR) is a binding protein for the thyroid hormone thyroxine (T4 ), retinol and β-amyloid peptide. TTR aids the transfer of T4 from the blood to the cerebrospinal fluid (CSF), but also prevents T4 loss from the blood-CSF barrier. It is however, unclear whether TTR affects the clearance of β-amyloid from the CSF. This study aimed to investigate roles of TTR in β-amyloid and T4 efflux from the CSF. Eight weeks old 129sv male mice were anaesthetized and their lateral ventricles were cannulated. Mice were infused with artificial CSF containing (125) I-T4 / (3) H-mannitol, or (125) I-Aβ40 / (3) H-inulin, in present or absent of TTR. Mice were decapitated at 2, 4, 8, 16, 24 minutes after injection. The whole brain was then removed and divided into different regions. The radioactivities in the brain were determined by liquid scintillation counting. At baseline, the net uptake of (125) I-T4 into the brain was significantly higher than that of (125) I-Aβ40, and the half time for efflux was shorter ((125) I-T4 : 5.16, (3) H-mannitol: 7.44; (125) I-Aβ40: 8.34, (3) H-inulin: 10.78; mins). The presence of TTR increased the half time for efflux of (125) I-T4 efflux, and caused a noticeable increase in the uptake of (125) I-T4 and (125) I-Aβ40 in the choroid plexus, whilst uptakes of (3) H-mannitol and (3) H-inulin remained similar to control experiments. This study indicates that thyroxine and amyloid peptide effuse from the CSF using different transporters. TTR binds to thyroxine and amyloid peptide to prevent the loss of thyroxine from the brain and redistribute amyloid peptide to the choroid plexus. This article is protected by copyright. All rights reserved.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. Alshehri B, D'Souza DG, Lee JY, Petratos S, Richardson SJ. The diversity of mechanisms influenced by transthyretin in neurobiology: development, disease and endocrine disruption. J. Neuroendocrinol. 2015; 27: 303-23.
    • 2. Dickson PW, Schreiber G. High levels of messenger RNA for transthyretin (prealbumin) in human choroid plexus. Neurosci. Lett. 1986; 66: 311-5.
    • 3. Dickson PW, Aldred AR, Marley PD, Bannister D, Schreiber G. Rat choroid plexus specializes in the synthesis and the secretion of transthyretin (prealbumin). Regulation of transthyretin synthesis in choroid plexus is independent from that in liver. J. Biol. Chem. 1986; 261: 3475-8.
    • 4. Fung WP, Thomas T, Dickson PW et al. Structure and expression of the rat transthyretin (prealbumin) gene. J. Biol. Chem. 1988; 263: 480-8.
    • 5. Hu S, Loo JA, Wong DT. Human body fluid proteome analysis. Proteomics 2006; 6: 6326-53.
    • 6. Southwell BR, Duan W, Alcorn D et al. Thyroxine transport to the brain: role of protein synthesis by the choroid plexus. Endocrinol. 1993; 133: 2116-26.
    • 7. Richardson SJ, Wijayagunaratne RC, D'Souza DG, Darras VM, van Herck SLJ. Transport of thyroid hormones via the choroid plexus into the brain: the roles of transthyretin and throid hormone transmemebrane transporters. Frontiers. Neurosci. 2005; 9: 1-8.
    • 8. Sousa JC, de Escobar GM, Oliveira P, Saraiva MJ, Palha JA. Transthyretin is not necessary for thyroid hormone metabolism in conditions of increased hormone demand. J.
    • 9. Palha JA, Hays MT, Morreale de Escobar G, Episkopou V, Gottesman ME, Saraiva MJ. Transthyretin is not essential for thyroxine to reach the brain and other tissues in transthyretin-null mice. Am. J. Physiol. 1997; 272: E485-93.
    • 10. Mendel CM. The free hormone hypothesis: a physiologically based mathematical model. Endocr. Rev. 1989; 10: 232-74.
    • 11. Kassem NA, Deane R, Segal MR, Preston JE. Role of transthyretin in thyroxine transfer from cerebrospinal fluid to brain and choroid plexus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006; 291: R1310-5.
    • 12. Chen RL, Kassem NA, Preston JE. Dose-dependent transthyretin inhibition of T4 uptake from cerebrospinal fluid in sheep. Neurosci. Lett. 2006; 396: 7-11.
    • 13. Schwarzman AL, Gregori L, Vitek MP et al. Transthyretin sequesters amyloid beta protein and prevents amyloid formation. Proc. Natl. Acad. Sci. USA. 1994; 91: 8368-72.
    • 14. Li X, Zhang X, Ladiwala AR et al. Mechanisms of transthyretin inhibition of β- amyloid aggregation in vitro. J Neurosci. 2013; 33: 19423-33.
    • 15. Yang DT, Joshi G, Cho PY, Johnson JA, Murphy RM. Transthyretin as both a sensor and a scavenger of β-amyloid oligomers. Biochemistry 2013; 52: 2849-61.
    • 16. Cho PY, Joshi G, Boersma MD, Johnson JA, Murphy RM.A cyclic peptide mimic of the β-amyloid binding domain on transthyretin. ACS Chem Neurosci. 2015; 6: 778- 89.
    • 17. Du J, Murphy RM. Characterization of the interaction of β-amyloid with transthyretin monomers and tetramers. Biochemistry 2010; 49: 8276-89.
    • 18. Costa R, Ferreira-da-Silva F, Saraiva MJ, Cardoso I. Transthyretin protects against A-beta peptide toxicity by proteolytic cleavage of the peptide: a mechanism sensitive to the Kunitz protease inhibitor. PLoS One 2008; 3: e2899.
    • 19. Crossgrove JS, Li GT, Zheng W. The choroid plexus removes beta- amyloid from brain cerebrospinal fluid. Exp. Biol. Med. (Maywood) 2005; 230: 771- 6.
    • 20. Crossgrove JS, Smith EL, Zheng W. Macromolecules involved in production and metabolism of beta-amyloid at the brain barriers. Brain. Res. 2007; 1138: 187-95.
    • 21. Liz MA, Mar FM, Franquinho F, Sousa MM. Aboard transthyretin: from transport to cleavage. IUBMB Life 2010; 62: 429-35.
    • 22. Merched A, Serot JM, Visvikis S, Aguillon D, Faure G, Siest G. Apolipoprotein E, transthyretin and actin in the CSF of Alzheimer's patients: relation with the senile plaques and cytoskeleton biochemistry. FEBS Lett. 1998; 425: 225-8.
    • 23. Stein TD, Johnson JA. Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. J. Neurosci. 2002; 22: 7380-8.
    • 24. Serot JM, Christmann D, Dubost T, Couturier M. Cerebrospinal fluid transthyretin: aging and late onset Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 1997; 63: 506-8.
    • 25. Castaño EM, Roher AE, Esh CL, Kokjohn TA, Beach T. Comparative proteomics of cerebrospinal fluid in neuropathologically - confirmed Alzheimer's disease and non-demented elderly subjects. Neurol. Res. 2006; 28:155-63.
    • 26. Gloeckner SF, Meyne F, Wagner F et al. Quantitative analysis of transthyretin, tau and amyloid-beta in patients with dementia. J. Alzheimers Dis. 2008; 14: 17-25.
    • 27. Hansson SF, Andréasson U, Wall M et al. Reduced levels of amyloid-betabinding proteins in cerebrospinal fluid from Alzheimer's disease patients. J. Alzheimers Dis. 2009; 16: 389-97.
    • 28. Schultz K, Nilsson K, Nielsen JE et al. Transthyretin as a potential CSF biomarker for Alzheimer's disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors. Eur. J. Neurol. 2010; 17: 456-60.
    • 29. Zibara K, El-Zein A, Joumaa W, El-Sayyad M, Mondello S, Kassem N. Thyroxine transfer from cerebrospinal fluid into choroid plexus and brain is affected by brefeldin A, low sodium, BCH, and phloretin, in ventriculo-cisternal perfused rabbits. Front Cell Dev Biol. 2015; 3: 60.
    • 30. Zheng W, Deane R, Redzic Z, Preston JE, Segal MB. Transport of [L125I]thyroxine by in situ perfused ovine choroid plexus: inhibition by lead exposure. J Toxicol Environ Health A. 2003; 66 :435-51.
    • 31. Sousa JC, Grandela C, Fernández-Ruiz J et al. Transthyretin is involved in depression-like behaviour and exploratory activity. J. Neurochem. 2004; 88: 1052-8.
    • 32. Buxbaum JN, Roberts AJ, Adame A, Masliah E. Silencing of murine transthyretin and retinol binding protein genes has distinct and shared behavioral and neuropathologic effects. Neuroscience. 2014; 275: 352-64.
    • 33. Deane R, Bell RD, Sagare A, Zlokovic BV. Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease. CNS. Neurol. Disord. Drug. Targets. 2009; 8: 16-30.
    • 34. Qosa H, Abuznait AH, Hill RA, Kaddoumi A. Enhanced brain amyloid-β clearance by rifampicin and caffeine as a possible protective mechanism against Alzheimer's disease. J Alzheimers Dis. 2012; 31: 151-65.
    • 35. Alemi M, Gaiteiro C, Ribeiro CA et al. Transthyretin participates in beta-amyloid transport from the brain to the liver- involvement of the low-density lipoprotein receptor-related protein 1? Sci Rep. 2016; 6: 20164.
    • 36. Ribeiro CA, Oliveira SM, Guido LF et al. Transthyretin stabilization by iododiflunisal promotes amyloid-β peptide clearance, decreases its deposition, and 37. Quintela T, Alves CH, Gonçalves I, Baltazar G, Saraiva MJ, Santos CR. 5Alphadihydrotestosterone up-regulates transthyretin levels in mice and rat choroid plexus via an androgen receptor independent pathway. Brain Res. 2008; 1229: 18-26.
    • 38. Vatassery GT, Quach HT, Smith WE, Benson BA, Eckfeldt JH. A sensitive assay of transthyretin (prealbumin) in human cerebrospinal fluid in nanogram amounts by ELISA. Clin Chim Acta. 1991; 197: 19-25.
    • 39. Price JM , Chi X, Hellermann G, Sutton ET. Physiological levels of beta-amyloid induce cerebral vessel dysfunction and reduce endothelial nitric oxide production.
    • 43. Elovaara I, Maury C, Palo J. Serum amyloid A protein, albumin and prealbumin in Alzheimer's disease and in demented patients with Down's syndrome. Acta Neurol. Scand. 1986; 74: 245-50.
    • 44. Riisøen H. Reduced prealbumin (transthyretin) in CSF of severely demented patients with Alzheimer's disease. Acta. Neurol. Scand. 1988; 78: 455-9.
    • 45. Weiner MW, Veitch DP, Aisen PS et al. Alzheimer's Disease neuroimaging initiative. 2014 Update of the Alzheimer's Disease neuroimaging initiative: a review of papers published since its inception. Alzheimers Dement. 2015;11(6):e1-e120.
    • 46. González-Marrero I, Giménez-Llort L, Johanson CE et al. Choroid plexus dysfunction impairs beta-amyloid clearance in a triple transgenic mouse model of Alzheimer's disease. Front. Cell. Neurosci. 2015; 9: 17.
    • 47. Silverberg GD, Mayo M, Saul T, Rubenstein E, McGuire D. Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol. 2003; 2: 506-11.
    • 48. Shuvaev VV, Laffont I, Serot JM, Fujii J, Taniguchi N, Siest G. Increased protein glycation in cerebrospinal fluid of Alzheimer's disease. Neurobiol. Aging 2001; 22: 397-402.
    • 49. Kuchler-Bopp S, Dietrich JB, Zaepfel M, Delaunoy JP. Receptor-mediated endocytosis of transthyretin by ependymoma cells. Brain Res. 2000; 870: 185-94.
    • 50. Fujiyoshi M, Tachikawa M, Ohtsuki S et al. Amyloid-β peptide(1-40) elimination from cerebrospinal fluid involves low-density lipoprotein receptor-related protein 1 at the blood-cerebrospinal fluid barrier. J. Neurochem. 2011; 118: 407-15.
    • 51. Pascale CL, Miller MC, Chiu C et al. Amyloid-beta transporter expression at the blood-CSF barrier is age dependent. Fluids Barriers CNS 2011; 8: 21.
    • 52. Hammad SM, Ranganathan S, Loukinova E, Twal WO, Argraves WS. Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein receptor-related protein-2 / megalin. A mechanism to prevent pathological accumulation of amyloid beta-peptide. J. Biol. Chem. 1997; 272: 18644-9.
    • 53. Alvira-Botero X, Carro EM. Clearance of amyloid-beta peptide across the choroid plexus in Alzheimer's disease. Curr. Aging Sci. 2010; 3: 219-29.
    • 54. Gregory GC, Halliday GM. What is the dominant Abeta species in human brain tissue? A review. Neurotox. Res. 2005; 7: 29-41.
    • 55. Jan A, Hartley DM, Lashuel HA. Preparation and characterization of toxic Abeta aggregates for structural and functional studies in Alzheimer's disease research. Nat. Protoc. 2010; 5: 1186-209.
    • 56. Monro OR, Mackic JB, Yamada S et al. Substitution at codon 22 reduces clearance of Alzheimer's amyloid-beta peptide from the cerebrospinal fluid and prevents its transport from the central nervous system into blood. Neurobiol. Aging 2002; 23: 405-12.
  • No related research data.
  • No similar publications.

Share - Bookmark

Cite this article