17β-Estradiol Induces Transthyretin Expression in Murine Choroid Plexus via an Oestrogen Receptor Dependent Pathway
Oestrogen protects against AD by multiple mechanisms, including the enhancement of Aβ clearance. Transthyretin (TTR) is a homotetrameric protein mainly synthesized by the liver and choroid plexus (CP) of the brain that sequesters the amyloid beta (Aβ) peptide. In this study we examined the effects of 17β-estradiol (E2) on TTR protein and mRNA levels, in primary cultures of rat CP epithelial cells (CPEC) by Western blot and Real Time PCR, respectively. Moreover, the localization of oestrogen receptors alpha (ERα) and beta (ERβ) in response to E2 treatment was analysed by confocal microscopy in these cells. The expression of TTR, ERα and ERβ was also compared in the CP of castrated female mice treated with E2 to vehicle-treated animals by Real Time PCR. TTR concentration in the CSF of all these animals was measured by radioimmunoassay. E2 treatment induced TTR transcription and increased TTR protein content in CPEC. Pre-treatment with ICI 182,780 (ICI) abrogated E2-induced TTR expression suggesting that, TTR is up-regulated via an ER-dependent pathway. Confocal microscopy demonstrated extranuclear ERα and ERβ localization in untreated CPEC. Upon E2 treatment, translocation of ERα to the nucleus occurred, while ERβ remained in the cytosol. These data was concurrent with the up-regulation of TTR expression detected in the CP of castrated female mice subjected to E2 treatment. Our results highlight the importance of E2 on the regulation of TTR, which may participate in the oestrogen-induced decrease in Aβ levels and deposition described in the literature.
KeywordsChoroid plexus Transthyretin Oestrogen Cerebrospinal fluid Oestrogen receptor
- Aldred AR, Brack CM, Schreiber G (1995) The cerebral expression of plasma protein genes in different species. Comp Biochem Physiol 111:1–15Google Scholar
- Eckman EA, Adams SK, Troendle FJ, Stodola BA, Kahn MA, Fauq AH, Xiao HD, Bernstein KE, Eckman CB (2006) Regulation of steady-state beta-amyloid levels in the brain by neprilysin and endothelin-converting enzyme but not angiotensin-converting enzyme. J Biol Chem 281:30471–30478. doi:10.1074/jbc.M605827200 PubMedCrossRefGoogle Scholar
- Schwarzman AL, Gregori L, Vitek MP, Lyubski S, Strittmatter WJ, Enghilde JJ, Bhasin R, Silverman J, Weisgraber KH, Coyle PK et al (1994) Transthyretin sequesters amyloid beta protein and prevents amyloid formation. Proc Natl Acad Sci USA 91:8368–8372. doi:10.1073/pnas.91.18.8368 PubMedCrossRefGoogle Scholar
- Schwarzman AL, Tsiper M, Gregori L, Goldgaber D, Frakowiak J, Mazur-Kolecka B, Taraskina A, Pchelina S, Vitek MP (2005) Selection of peptides binding to the amyloid b-protein reveals potential inhibitors of amyloid formation. Amyloid 12:199–209. doi:10.1080/13506120500350762 PubMedCrossRefGoogle Scholar
- Tang YP, Haslam SZ, Conrad SE, Sisk CL (2004) Estrogen increases brain expression of the mRNA encoding transthyretin, an amyloid beta scavenger protein. J Alzheimers Dis 6:413–420. discussion 443–419Google Scholar