Estradiol inhibits GSK3 and regulates interaction of estrogen receptors, GSK3, and beta-catenin in the hippocampus.

Estrogens regulate a wide set of neuronal functions such as gene expression, survival and differentiation in a manner not very different from that exerted by neurotrophins or by growth factors. The best-studied hormonal action is the transcriptional activation mediated by estrogen receptors. However, the direct effects of estrogen on growth factor signaling have not been well clarified. The present data show that estradiol, in vivo, induces a transient activation of GSK3 in the adult female rat hippocampus, followed by a more sustained inhibition, as inferred from phosphorylation levels of Tau. Similar data was obtained from cultured hippocampal neurons when treated with the hormone. The transient activation was confirmed by direct measure of GSK3 kinase activity. In addition, our results show a novel complex of estrogen receptor alpha, GSK3, and beta-catenin. The presence of the hormone removes beta-catenin from this complex. There is a second complex, also affected by estradiol, in which Tau is associated with GSK3, beta-catenin, and elements of the PI3 kinase complex. Considering the role of GSK3 in neurodegeneration, our data suggest that part of the neuroprotective effects of estrogen may be due to the control of GSK3.