Greco Steven J, Sarkar Sraboni, Casadesus Gemma, Zhu Xiongwei, Smith Mark A, Ashford J Wesson, Johnston Jane M, Tezapsidis Nikolaos
Research & Development, Neurotez, Inc., Bridgewater, NJ 08807, USA.
Neurosci Lett. 2009 May 22;455(3):191-4. doi: 10.1016/j.neulet.2009.03.066. Epub 2009 Mar 25.
We have previously demonstrated that Leptin reduces extracellular amyloid beta (Abeta) protein both in vitro and in vivo, and intracellular tau phosphorylation in vitro. Further, we have shown that these effects are dependent on activation of AMP-activated protein kinase (AMPK) in vitro. Herein, we investigated downstream effectors of AMPK signaling directly linked to tau phosphorylation. One such target, of relevance to Alzheimer's disease (AD), may be GSK-3beta, which has been shown to be inactivated by Leptin. We therefore dissected the role of GSK-3beta in mediating Leptin's ability to reduce tau phosphorylation in neuronal cells. Our data suggest that Leptin regulates tau phosphorylation through a pathway involving both AMPK and GSK-3beta. This was based on the following: Leptin and the cell-permeable AMPK activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), reduced tau phosphorylation at AD-relevant sites similarly to the GSK-3beta inhibitor, lithium chloride (LiCl). Further, this reduction of tau phosphorylation was mimicked by the downregulation of GSK-3beta, achieved using siRNA technology and antagonized by the ectopic overexpression of GSK-3beta. These studies provide further insight into Leptin's mechanism of action in suppressing AD-related pathways.
我们之前已经证明，瘦素在体外和体内均可降低细胞外淀粉样β蛋白（Aβ），并在体外降低细胞内tau蛋白磷酸化。此外，我们还表明，这些作用在体外依赖于AMP激活的蛋白激酶（AMPK）的激活。在此，我们研究了与tau蛋白磷酸化直接相关的AMPK信号传导的下游效应器。与阿尔茨海默病（AD）相关的一个这样的靶点可能是糖原合成酶激酶-3β（GSK-3β），已有研究表明它会被瘦素失活。因此，我们剖析了GSK-3β在介导瘦素降低神经元细胞中tau蛋白磷酸化能力方面的作用。我们的数据表明，瘦素通过一条涉及AMPK和GSK-3β的途径调节tau蛋白磷酸化。这基于以下几点：瘦素和细胞可渗透的AMPK激活剂5-氨基咪唑-4-甲酰胺核苷（AICAR）与GSK-3β抑制剂氯化锂（LiCl）类似，均可降低AD相关位点的tau蛋白磷酸化。此外，使用小干扰RNA（siRNA）技术下调GSK-3β可模拟这种tau蛋白磷酸化的降低，而GSK-3β的异位过表达则可拮抗这种降低。这些研究进一步深入了解了瘦素在抑制AD相关途径中的作用机制。
