title: 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.
abstract: 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 ERbeta. We found that 17beta-estradiol (17betaE(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, 17betaE(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. 17betaE(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 ERalpha because the selective ERalpha agonist propylpyrazole-triol determined a much greater increase of seladin-1 expression than the ERbeta 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.
authors.affiliation: Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Benvenuti
authors.forename: Paola
authors.initials: P
authors.lastname: Luciani
authors.forename: Gabriella Barbara
authors.initials: GB
authors.lastname: Vannelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Gelmini
authors.forename: Elisa
authors.initials: E
authors.lastname: Franceschi
authors.forename: Mario
authors.initials: M
authors.lastname: Serio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Peri
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology; D019098:Telomerase / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C437069:3beta-hydroxysterol delta24-reductase; C499055:DHCR24 protein, human; D019098:Telomerase