To determine the effect on tau phosphorylation in vitro Alvarez de la Rosa et al. analyzed the phosphorylation state of tau in neuroblastoma cells and in primary cortical neuron cultures in response to okadaic acid in the presence and absence of estradiol. Okadaic acid is a selective inhibitor of protein phosphatase 1 and 2 that produces changes tau phosphorylation as well as changes in cytoskeletal structure reminiscent of neurodegeneration. Intracerebral injections of okadaic acid in rats results in the formation of tau paired helical filament-like phosphorylation similar that found in neurofibrillary tangles of Alzheimer’s disease [4,73]. Estradiol pretreatment resulted in a reduction in the amount of proline-directed phosphorylation of tau in basal cultures and inhibited the okadaic acid-induced hyperphosphorylation of the proline-directed sites [2]. Additionally, estradiol inhibited the okadaic acid-induced hyperphosphorylation of tau at non-proline-directed sites that were unaffected by estradiol by itself [2].