Department of Clinical Physiopathology, Endocrine Unit, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe), University of Florence, Florence, Italy.
Neuroscience. 2011 Sep 15;191:107-17. doi: 10.1016/j.neuroscience.2011.03.011. Epub 2011 Mar 22.
Alzheimer's disease (AD), the most common neurodegenerative disease associated with aging, is still an incurable condition. Although in vitro evidence strongly indicates that estrogens exert neurotrophic and neuroprotective effects, the role of this class of hormones in the treatment of AD is still a debated issue. In 2000 a new gene, named seladin-1 (for SELective Alzheimer's Disease INdicator-1), was identified and found to be down regulated in vulnerable brain regions in AD. Seladin-1 was considered a novel neuroprotective factor, because of its anti-apoptotic activity. Subsequently, it was demonstrated that seladin-1 has also enzymatic activity [3-β-hydroxysterol delta-24-reductase, (DHCR24)], which catalyzes the synthesis of cholesterol from desmosterol. The amount of membrane cholesterol may play an important role both in protecting neuronal cells against toxic insults and in inhibiting the production of β-amyloid. We demonstrated that seladin-1 overexpression increases the amount of membrane cholesterol and induces resistance against β-amyloid aggregates in neuroblastoma cells, whereas a specific inhibitor of DHCR24 increased cell vulnerability. We also hypothesized that seladin-1 might be a mediator of the neuroprotective effects of estrogens. We first demonstrated that, in human fetal neuroepithelial cells (FNC), 17β-estradiol, raloxifene, and tamoxifen exert protective effects against β-amyloid toxicity and oxidative stress. In addition, these molecules significantly increased the expression of seladin-1 and the amount of cell cholesterol. Then, we showed that, upon seladin-1 silencing, the protective effects of estrogens were abolished, thus indicating this factor as a fundamental mediator of estrogen-mediated neuroprotection, at least in FNC cells. Furthermore, we detected the presence of functionally active half-palindromic estrogen responsive elements upstream the coding region of the seladin-1 gene. Overall, our results indicate that seladin-1 may be viewed as a multi-faceted protein, which conjugates both the neuroprotective properties of estrogens and the important functions of cholesterol in maintaining brain homeostasis. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.
阿尔茨海默病（AD）是与衰老相关的最常见的神经退行性疾病，仍然是一种无法治愈的疾病。尽管体外证据强烈表明雌激素具有神经营养和神经保护作用，但这类激素在 AD 治疗中的作用仍存在争议。2000 年，一种新的基因，命名为 seladin-1（选择性阿尔茨海默病指示剂-1 的缩写），被鉴定出来，并在 AD 易受影响的大脑区域中发现其表达下调。Seladin-1 被认为是一种新型的神经保护因子，因为它具有抗细胞凋亡的活性。随后，研究表明 seladin-1 还具有酶活性[3-β-羟甾醇 δ-24-还原酶，（DHCR24）]，可催化从 desmosterol 合成胆固醇。膜胆固醇的含量可能在保护神经元细胞免受毒性损伤和抑制β-淀粉样蛋白的产生方面都起着重要作用。我们证明，seladin-1 的过表达增加了膜胆固醇的含量，并诱导神经母细胞瘤细胞抵抗β-淀粉样蛋白聚集，而 DHCR24 的特异性抑制剂则增加了细胞的脆弱性。我们还假设 seladin-1 可能是雌激素神经保护作用的介质。我们首先证明，在人胎儿神经上皮细胞（FNC）中，17β-雌二醇、raloxifene 和 tamoxifen 对β-淀粉样蛋白毒性和氧化应激具有保护作用。此外，这些分子显著增加了 seladin-1 的表达和细胞胆固醇的含量。然后，我们表明，在沉默 seladin-1 后，雌激素的保护作用被消除，这表明该因子是雌激素介导的神经保护的基本介质，至少在 FNC 细胞中是这样。此外，我们在 seladin-1 基因的编码区上游检测到具有功能活性的半回文雌激素反应元件。总的来说，我们的结果表明，seladin-1 可以被视为一种具有多方面功能的蛋白质，它结合了雌激素的神经保护特性和胆固醇在维持大脑内稳态中的重要功能。本文是一个特刊的一部分，题目是：神经活性甾体：聚焦人类大脑。
