17beta-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 Abeta clearance. Transthyretin (TTR) is a homotetrameric protein mainly synthesized by the liver and choroid plexus (CP) of the brain that sequesters the amyloid beta (Abeta) peptide. In this study we examined the effects of 17beta-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 (ERalpha) and beta (ERbeta) in response to E2 treatment was analysed by confocal microscopy in these cells. The expression of TTR, ERalpha and ERbeta 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 ERalpha and ERbeta localization in untreated CPEC. Upon E2 treatment, translocation of ERalpha to the nucleus occurred, while ERbeta 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 Abeta levels and deposition described in the literature.
Quintela
T
T
Health Sciences Research Centre, CICS, University of Beira Interior, Av Infante D Henrique, Covilhã, Portugal.
Gonçalves
I
I
Baltazar
G
G
Alves
C H
CH
Saraiva
M J
MJ
Santos
C R A
CR
D000818:Animals; D002478:Cells, Cultured; D002831:Choroid Plexus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011228:Prealbumin; D004958:Estradiol