Estrogen exerts neuroprotective effects and reduces -amyloid accumulation in models of Alzheimer's disease (AD). A few years ago, a new neuroprotective gene, i.e. seladin-1 (for Selective Alzheimer's Disease indicator-1) was identified and found to be down regulated in AD vulnerable brain regions. Seladin-1 inhibits the activation of caspase-3, a key modulator of apoptosis. In addition, it has been demonstrated that the seladin-1 gene encodes 3-beta-hydroxysterol delta-24-reductase, that catalyzes the synthesis of cholesterol from desmosterol. We have demonstrated previously that in fetal neuroepithelial cells (FNC) 17-estradiol (17E₂), raloxifene and tamoxifenexert neuroprotective effects and increase the expression of seladin-1. The aim of the present study was to elucidate whether seladin-1 is directly involved in estrogen-mediated neuroprotection. Using the small interfering RNA methodology, significantly reduced levels of seladin-1 mRNA and protein were obtained in FNC. Seladin-1 silencing determined the loss of the protective effect of 17E₂ against -amyloid and oxidative stress toxicity and caspase-3 activation. A computer assisted analysis revealed the presence of half-palindromic estrogen responsive elements (EREs) upstream the coding region of the seladin-1 gene. A 1490 bp region was cloned in a luciferase reporter vector, which was transiently co-transfected with the estrogen receptor in CHO cells. The exposure to 17E₂, raloxifene, tamoxifen and the soy isoflavones genistein and zearalonone increased luciferase activity, thus suggesting a functional role for the half EREs of the seladin-1 gene. Our data provide for the first time a direct demonstration that seladin-1 may be considered a fundamental mediator of the neuroprotective effects of estrogen.