5Alpha-dihydrotestosterone up-regulates transthyretin levels in mice and rat choroid plexus via an androgen receptor independent pathway.
Transthyretin (TTR) is a 55 kDa plasma homotetrameric protein mainly synthesized in the liver and choroid plexuses (CPs) of the brain that, functions as a carrier for thyroxin and retinol binding protein. It sequesters amyloid beta (Abeta) peptide, and TTR levels in the cerebrospinal fluid (CSF) appear to be inversely correlated with Alzheimer's disease (AD) onset and progression. Androgen deprivation increases plasma Abeta levels, which indicate that androgens may reduce the levels of soluble Abeta, the peptide widely implicated in the initiation of AD pathogenesis; however, the underlying mechanisms are still poorly understood. In this study we examined the effects of 5alpha-dihydrotestosterone (DHT) on TTR protein and mRNA levels, in primary cultures of rat CPs epithelial cells (CPEC) by Western blot, and real time PCR, respectively. Moreover, TTR concentrations were measured in the CSF of castrated wild-type, and transgenic mice expressing human TTR subjected to DHT treatment, by radioimmunoassay and ELISA, respectively. TTR mRNA expression was also compared in the CPs, of the animals from each experimental group by real time PCR. DHT treatment increased TTR protein levels in CPEC, and induced TTR transcription in these cells. The combination of flutamide with DHT in the treatment of CPEC did not abrogate DHT-induced TTR levels, suggesting that TTR is up-regulated via an androgen receptor independent pathway. In the CPs of both mice strains, DHT also increased TTR mRNA levels, but no significant differences in TTR protein levels were detected in the CSF of these animals. These findings open a wide range of possibilities for future studies on Abeta deposition and cognitive function, in response to androgen induction of TTR in animal models of AD.
Quintela
T
T
Health Sciences Research Centre-CICS, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal.
Alves
C H
CH
Gonçalves
I
I
Baltazar
G
G
Saraiva
M J
MJ
Santos
C R A
CR
D000367:Age Factors; D000704:Analysis of Variance; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000884:Anthropology, Cultural; D002831:Choroid Plexus / Q000166:cytology / Q000187:drug effects*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
D059002:Androgen Receptor Antagonists; D000728:Androgens; D011228:Prealbumin; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D005485:Flutamide