Alzheimer's disease is the most frequent neurodegenerative disorder in the aged population and is characterized by the deposition of the 40/42-residue amyloid beta protein (A beta), a proteolytic fragment of the beta-amyloid precursor protein (APP). Recently, it has been shown that physiological doses of estradiol reduce the generation of endogenous A beta in primary cortical neurons. Here we investigate the influence of estrogen in amyloidogenesis and sAPP alpha secretion in the CNS. By means of primary cortical neurons overexpressing humanized APP(695) bearing the Swedish mutation (hAPP(695sw)), we analyzed APP maturation in the absence or in the presence of estrogen. We show that estrogen at a 2 mu M concentration increases the release of the neuroprotective sAPP alpha fragment but does not reduce the release of A beta in primary neurons overexpressing the Swedish-mutated form of APP, Furthermore, neurons cocultured with astrocytic cells or grown with astrocytes conditioned media do not exhibit the estrogen-induced increase in sAPP alpha secretion. Altogether, our data indicate that astrocytes interfere with estrogen in the regulation of sAPP alpha secretion, probably via secreted factor(s).