Relationship between oestrogen and cholesterol in neuroprotection
Alzheimers disease (AD), the most common neurodegenerative disease associated with ageing, is still an incurable condition. Although in vitro evidence strongly indicates that oestrogen exerts 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 Alzheimers 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 (3β-hydroxysterol delta-24-reductase, (DHCR24)), which catalyzes the synthesis of cholesterol from desmosterol. There is evidence that an appropriate amount of membrane cholesterol is important in order to generate a barrier against toxic insults and also to prevent the production of β-amyloid. We demonstrated that seladin-1 overexpression increases the amount of membrane cholesterol and determines resistance against β-amyloid aggregates in neuroblastroma 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 oestrogen. We first demonstrated that, in human fetal neuroepithelial cells (FNC), 17β-oestradiol, 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 oestrogen were abolished, thus indicating that this factor is a fundamental mediator of oestrogen-mediated neuroprotection, at least in FNC cells. Furthermore, we detected the presence of functionally active half-palindromic oestrogen 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 oestrogen and the important functions of cholesterol in maintaining brain homeostasis.