Although the mechanism by which estradiol regulates tau phosphorylation cannot be determined by these studies, there is evidence that estradiol can modulate the requisite kinases, which can affect the balance between kinases and phosphatases. We and others have shown that estradiol can activate many signaling transduction pathways such as the mitogen activated protein kinase (MAPK), Akt and phosphoinositol-3 kinase (PI-3K) pathways [136,108,137,133].