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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

Endocrine Unit (S.B., P.L., E.F., M.S., A.P.) and Clinical Biochemistry Unit (S.G.), Department of Clinical Physiopathology, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative, and Neoplastic Disorders, University of Florence; and Department of Anatomy, Histology, and Forensic Medicine (G.B.V.), University of Florence, 50139 Florence, Italy

Address all correspondence and requests for reprints to: Alessandro Peri, M.D., Ph.D., Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy. E-mail: a.peri{at}dfc.unifi.it.

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)- and ERß. We found that 17ß-estradiol (17ßE₂) and the selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen exerted neuroprotective effects, which were independent of cell proliferation, by increasing resistance against ß-amyloid-induced toxicity, with the exception of the highest concentrations of raloxifene (10 and 100 nM). In addition, 17ßE₂ 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. 17ßE₂ (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 because the selective ER agonist propylpyrazole-triol determined a much greater increase of seladin-1 expression than the ERß 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.

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