Natural Products Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute, Kangneung 210-340, Republic of Korea.
Neuropharmacology. 2010 Nov;59(6):542-50. doi: 10.1016/j.neuropharm.2010.07.020. Epub 2010 Aug 12.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive loss of neurons and production of β-amyloid proteins (Aβ). Hyperphosphorylation of tau protein is proposed to be an early event for the evolution of AD, and may play an important role in Aβ-induced neurodegeneration. Icariin, a flavonoid compound from the herb Epimedium brevicornum Maxim, exerts a protective effect on learning and memory abilities in Aβ(25-35)-induced AD rats. However, the molecular mechanism of icariin-induced neuroprotective effect against tau protein hyperphosphorylation, which is one of the most representative hallmarks in AD, is still unknown. In the present study, we investigated the inhibitory effect of icariin on Aβ(25-35)-induced tau protein hyperphosphorylation on PC12 cells. The results showed that treatment with icariin significantly decreased Aβ(25-35)-induced cytotoxicity and apoptosis rate through inhibiting tau protein hyperphosphorylation at Ser396, Ser404 and Thr205 sites, respectively. Mechanism study showed that icariin could activate PI3K/Akt signaling pathway, resulting in an inhibitory effect on glycogen synthase kinase (GSK)-3β, which is an important kinase response for tau protein hyperphosphorylation in the development of AD. These observations indicate that icariin is capable of attenuating Aβ(25-35)-induced tau protein hyperphosphorylation and promoting survival of neuronal cells, meanwhile also provide some insights into the potential signaling pathway that is involved. Thus, this study promises a great potential agent for Alzheimer's disease and other tau pathology-related neuronal degenerative diseases.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是神经元逐渐丧失和β-淀粉样蛋白（Aβ）的产生。过度磷酸化的 tau 蛋白被认为是 AD 发展的早期事件，可能在 Aβ诱导的神经退行性变中发挥重要作用。淫羊藿素是来自草药淫羊藿的一种黄酮类化合物，对 Aβ（25-35）诱导的 AD 大鼠的学习和记忆能力具有保护作用。然而，淫羊藿素诱导 tau 蛋白过度磷酸化的神经保护作用的分子机制，这是 AD 最具代表性的特征之一，仍然未知。在本研究中，我们研究了淫羊藿素对 Aβ（25-35）诱导的 PC12 细胞 tau 蛋白过度磷酸化的抑制作用。结果表明，淫羊藿素通过抑制 tau 蛋白在 Ser396、Ser404 和 Thr205 位点的过度磷酸化，显著降低了 Aβ（25-35）诱导的细胞毒性和细胞凋亡率。机制研究表明，淫羊藿素可以激活 PI3K/Akt 信号通路，从而抑制糖原合酶激酶（GSK）-3β，这是 AD 发展中 tau 蛋白过度磷酸化的重要激酶反应。这些观察结果表明，淫羊藿素能够减轻 Aβ（25-35）诱导的 tau 蛋白过度磷酸化，促进神经元细胞的存活，同时也为潜在的信号通路提供了一些见解。因此，这项研究为阿尔茨海默病和其他与 tau 病理相关的神经退行性疾病提供了一种很有前途的治疗药物。
