Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Brain Res. 2010 Jul 23;1345:176-81. doi: 10.1016/j.brainres.2010.04.074. Epub 2010 May 7.
One of the pathological hallmarks of Alzheimer's disease (AD) is neurofibrillary tangles (NFTs), which are composed of abnormally hyperphosphorylated tau, but the mechanism of tau hyperphosphorylation in AD is still unclear. To investigate the effects of estrogens on tau phosphorylation, SH-SY5Y cells were treated with okadaic acid (OA), a serine/threonine phosphatase inhibitor, to induce tau phosphorylation and the effects of estrogen were observed by co-treatment with 17beta-estradiol (E2). We found that OA induced in vitro tau hyperphosphorylation, which was prevented by E2 in a dose-dependent manner. This effect of E2 was partially blocked by an estrogen receptor (ER) antagonist, ICI 182,780. In addition to tau hyperphosphorylation, inhibition of serine/threonine phosphorylation induced upregulation of cdk5 levels, which was attenuated by E2 in a manner that was counteracted by ICI 182,780. Our results show that cdk5 is involved in OA-induced tau hyperphosphorylation, and estrogens ameliorate the tau hyperphosphorylation, which may be mediated in part by ER.
阿尔茨海默病（AD）的病理学标志之一是神经原纤维缠结（NFTs），其由异常过度磷酸化的 tau 组成，但 AD 中 tau 过度磷酸化的机制仍不清楚。为了研究雌激素对 tau 磷酸化的影响，用丝氨酸/苏氨酸磷酸酶抑制剂岗田酸（OA）处理 SH-SY5Y 细胞，诱导 tau 磷酸化，并通过与 17β-雌二醇（E2）共同处理来观察雌激素的作用。我们发现 OA 在体外诱导 tau 过度磷酸化，E2 以剂量依赖性方式阻止了这种作用。雌激素受体（ER）拮抗剂 ICI 182,780 部分阻断了这种 E2 作用。除了 tau 过度磷酸化之外，抑制丝氨酸/苏氨酸磷酸化诱导 cdk5 水平上调，E2 以对抗 ICI 182,780 的方式减弱了这种上调。我们的结果表明，cdk5 参与了 OA 诱导的 tau 过度磷酸化，而雌激素改善了 tau 过度磷酸化，这可能部分通过 ER 介导。
