Estrogen and Selective Estrogen Receptor Modulators Exert

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 Downloaded from https://academic.oup.com/jcem/article/90/3/1775/2836938 by guest on 25 September 2021

Susanna Benvenuti, Paola Luciani, Gabriella Barbara Vannelli, Stefania Gelmini, Elisa Franceschi, Mario Serio, and Alessandro Peri 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

According to the fact that Alzheimer’s disease (AD) is more catalytic subunit of telomerase. Furthermore, we evaluated common in postmenopausal women, estrogen treatment has by quantitative real-time RT-PCR whether estrogen/SERMs been proposed. Experimental studies, still mostly performed modulate the expression of the recently discovered seladin-1 using animal models, demonstrated that estrogen exerts neu- (selective AD indicator-1) gene, which exerts neuroprotective roprotective effects. We previously established neuroblast effects and is down-regulated in AD-vulnerable brain regions. ␤ long-term cell cultures from human fetal olfactory epithelium. 17 E2 (100 pM to 100 nM) and SERMs (1 nM) significantly in- In the present study, we addressed the role of estrogen in creased the amount of seladin-1 mRNA. Conversely, 10 and 100 these unique human cells, which express both the estrogen nM raloxifene reduced the expression of seladin-1. The effect ␣ ␤ ␤ ␤ ␣ receptor (ER)- and ER . We found that 17 -estradiol (17 E2) of estrogen appears mainly mediated by ER because the se- and the selective estrogen receptor modulators (SERMs) lective ER␣ agonist propylpyrazole-triol determined a much raloxifene and tamoxifen exerted neuroprotective effects, greater increase of seladin-1 expression than the ER␤ agonist which were independent of cell proliferation, by increasing diarylpropionitrile. Our results add new evidence, using hu- resistance against ␤-amyloid-induced toxicity, with the ex- man neuronal cells, for a beneficial effect of estrogen in pre- ception of the highest concentrations of raloxifene (10 and 100 venting neurodegenerative diseases and suggest for the first ␤ nM). In addition, 17 E2 exposure protected from oxidative time that seladin-1 may mediate this effect. (J Clin Endocrinol stress, reduced apoptosis, and increased the expression of the Metab 90: 1775–1782, 2005)

HERE IS in vitro evidence, still mostly using animal mental failure in humans, is characterized by a progressive T models, that estrogen exerts neurotrophic and neuro- impairment of cognitive functions, such as memory and lan- protective effects by stimulating the expression of neurotro- guage. The histopathological hallmark of AD is represented phins and cell-survival factors, enhancing synaptic plasticity, by the accumulation of extracellular ␤-amyloid plaques and and acting as an antioxidant factor (reviewed in Refs. 1 and intracellular neurofibrillary tangles, which are responsible 2). Besides the hypothalamus, which is the traditional site of for a complex inflammatory response leading to neuronal estrogen action in the brain, both the estrogen receptor degeneration and cell death (reviewed in Ref. 3). Because (ER)-␣ and ER␤ have been found, for instance, in the neo- there is still no reliable way of predicting the onset of the cortex and hippocampus, two brain areas highly involved in disease and curing it, AD constitutes a profound heal