Membrane cholesterol as a mediator of the neuroprotective effects of estrogens

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.

Potential molecular targets, which may confer neuroprotection via the production of neuroprotective steroids. Seladin-1 may be addressed as an additional target, together with StAR, TSPO and aromatase. In fact, seladin-1 induces the synthesis of cholesterol and hence of estrogens, which in turn stimulate the expression of this neuroprotective factor. In addition, an optimal amount of cholesterol into the cell membrane is needed to warrant neuroprotection.Figure optionsDownload high-quality image (94 K)Download as PowerPoint slideHighlights▶Alzheimer's disease is still an incurable condition. ▶Estrogens and IGF-1 have neuroprotective effects, as assessed in vitro and in vivo. ▶The amount of membrane cholesterol appears crucial for neuroprotection. ▶Seladin-1 is a mediator of the protective effects of estrogens, IGF-1, and cholesterol.