Estrogen increases brain expression of the mRNA encoding transthyretin, an amyloid beta scavenger protein

Estrogen replacement therapy in postmenopausal women is associated with a reduced risk of Alzheimer's Disease (AD). The multiple mechanisms by which estrogen protects against AD are still unknown. To conduct a broad screen for estrogen-regulated AD-related genes in the brain, we used cDNA array assays of brain mRNA samples from ovariectomized (ovx) adult female mice treated with either 17beta-estradiol or vehicle at 1 or 5 weeks post-ovx. The gene encoding transthyretin (TTR), which has been reported to scavenge amyloid beta peptides and reduce amyloid plaque formation, is increased by estradiol treatment at both 1 and 5 weeks post-ovx. Northern blot analyses and RNase protection assays performed on whole brain samples obtained from estradiol- or vehicle-treated mice confirmed the cDNA array assays showing a significant increase in TTR mRNA with estradiol treatment. Qualitative in situ hybridization or immunocytochemistry performed on brain sections demonstrated that TTR mRNA is expressed only in choroid plexus and leptomeninges, and that both estrogen receptor proteins, alpha and beta, are present in choroid plexus cells. These novel findings suggest that estrogen may reduce the risk of AD by acting on choroid plexus cells to increase TTR gene expression, leading to enhanced sequestration and reduced aggregation of amyloid beta peptides.