Estrogen and selective estrogen receptor modulators exert neuroprotective effects and stimulate the expression of selective Alzheimer's disease indicator-1, a recently discovered antiapoptotic gene, in human neuroblast long-term cell cultures

According to the fact that Alzheimer's disease ( AD) is more common in postmenopausal women, estrogen treatment has been proposed. Experimental studies, still mostly performed using animal models, demonstrated that estrogen exerts neuroprotective effects. We previously established neuroblast long-term cell cultures from human fetal olfactory epithelium. In the present study, we addressed the role of estrogen in these unique human cells, which express both the estrogen receptor ( ER)-alpha and ER beta. We found that 17 beta-estradiol (17 beta E-2) and the selective estrogen receptor modulators ( SERMs) raloxifene and tamoxifen exerted neuroprotective effects, which were independent of cell proliferation, by increasing resistance against beta-amyloid-induced toxicity, with the exception of the highest concentrations of raloxifene ( 10 and 100 nM). In addition, 17 beta E-2 exposure protected from oxidative stress, reduced apoptosis, and increased the expression of the catalytic subunit of telomerase. Furthermore, we evaluated by quantitative real-time RT-PCR whether estrogen/SERMs modulate the expression of the recently discovered seladin-1 ( selective AD indicator-1) gene, which exerts neuroprotective effects and is down-regulated in AD-vulnerable brain regions. 17 beta E-2 ( 100 pM to 100 nM) and SERMs ( 1 nM) significantly increased the amount of seladin-1 mRNA. Conversely, 10 and 100 nM raloxifene reduced the expression of seladin-1. The effect of estrogen appears mainly mediated by ER alpha because the selective ER alpha agonist propylpyrazole-triol determined a much greater increase of seladin-1 expression than the ER beta agonist diarylpropionitrile. Our results add new evidence, using human neuronal cells, for a beneficial effect of estrogen in preventing neurodegenerative diseases and suggest for the first time that seladin-1 may mediate this effect.